Carboxamide derivatives as muscarinic receptor antagonists

ABSTRACT

The invention relates to compounds of formula 
                         
processes and intermediates for their preparation, their use as muscarinic antagonists and pharmaceutical composition containing them.

CROSS-REFERENCE TO RELATED APPLICATIONS

Priority is claimed to U.S. provisional application Ser. No. 60/719,468,filed Sep. 21, 2005, U.S. provisional application Ser. No. 60/719,467,filed Sep. 21, 2005 and U.S. provisional application Ser. No.60/719,477, filed Sep. 21, 2005, all incorporated herein by reference.

BACKGROUND OF THE INVENTION

Cholinergic muscarinic receptors are members of the G-protein coupledreceptor super-family and are further divided into 5 subtypes, M₁ to M₅.Muscarinic receptor sub-types are widely and differentially expressed inthe body. Genes have been cloned for all 5 sub-types and of these, M₁,M₂ and M₃ receptors have been extensively pharmacologicallycharacterized in animal and human tissue. M₁ receptors are expressed inthe brain (cortex and hippocampus), glands and in the ganglia ofsympathetic and parasympathetic nerves. M₂ receptors are expressed inthe heart, hindbrain, smooth muscle and in the synapses of the autonomicnervous system. M₃ receptors are expressed in the brain, glands andsmooth muscle. In the airways, stimulation of M₃ receptors evokescontraction of airway smooth muscle leading to bronchoconstriction,while in the salivary gland M₃ receptor stimulation increases fluid andmucus secretion leading to increased salivation. M₂ receptors expressedon smooth muscle are understood to be pro-contractile while pre-synapticM₂ receptors modulate acetylcholine release from parasympathetic nerves.Stimulation of M₂ receptors expressed in the heart produces bradycardia.

Short and long-acting muscarinic antagonists are used in the managementof asthma and COPD; these include the short acting agents Atrovent®(ipratropium bromide) and Oxivent® (oxitropium bromide) and the longacting agent Spiriva® (tiotropium bromide). These compounds producebronchodilation following inhaled administration. In addition toimprovements in spirometric values, anti-muscarinic use in chronicobstructive pulmonary disease (COPD) is associated with improvements inhealth status and quality of life scores.

As a consequence of the wide distribution of muscarinic receptors in thebody, significant systemic exposure to muscarinic antagonists isassociated with effects such as dry mouth, constipation, mydriasis,urinary retention (all predominantly mediated via blockade of M₃receptors) and tachycardia (mediated by blockade of M₂ receptors). Acommonly reported side-effect following inhaled administration oftherapeutic dose of the current, clinically used non-selectivemuscarinic antagonists is dry-mouth and while this is reported as onlymild in intensity it does limit the dose of inhaled agent given.

Accordingly, there is still a need for improved M₃ receptor antagoniststhat would have an appropriate pharmacological profile, for example interm of potency, pharmacokinetics or duration of action. In thiscontext, the present invention relates to novel M₃ receptor antagonists.In particular, there is a need for M₃ receptor antagonists that wouldhave a pharmacological profile suitable for an administration by theinhalation route.

The scientific literature discloses many compounds having a muscarinicreceptor antagonist activity. As a matter of example, EP0948964A1discloses compounds of formula

in which R denotes a hydrogen atom, a halogen atom or a lower alkoxygroup.

SUMMARY OF THE INVENTION

The invention relates to a compound of formula (I)

wherein,

-   -   R¹ is CN or CONH₂;    -   A is selected from

wherein * and ** represent the attachment points, ** being linked to theoxygen,

-   -   R² and R³ are methyl, or, where A is a group of formula

R² and R³ may also together form with the carbon atom to which they arelinked a cyclopentane ring;

-   -   p is 0 or 1;    -   A¹ is selected from        -   a) phenyl optionally substituted with 1, 2 or 3 groups            independently selected from halo, CN, CF₃, OR⁴, SR⁴, OCF₃,            (C₁-C₄)alkyl and phenyl optionally substituted with OH;        -   b) naphthyl optionally substituted with 1 or 2 groups            independently selected from halo, CN, CF₃, OR⁴, SR⁴, OCF₃            and (C₁-C₄)alkyl;        -   c) a 9 or 10-membered bicyclic aromatic heterocyclic group,            containing from 1, 2 or 3 heteroatoms independently selected            from O, S or N, said heterocyclic group being optionally            substituted with 1 or 2 substituents independently selected            from OR⁴, (C₁-C₄)alkyl and halo;    -   R⁴ is H or (C₁-C₄)alkyl;        or, if appropriate, the pharmaceutically acceptable salts or        solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the here above general formula (I), (C₁-C₄)alkyl denote a straightchain or branched group containing 1, 2, 3 or 4 carbon atoms. This alsoapplies if they carry substituents or occur as substituents of otherradicals, for example in O—(C₁-C₄)alkyl radicals, S—(C₁-C₄)alkylradicals etc . . . . Examples of suitable (C₁-C₄)alkyl radicals aremethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl . . . . Examples of suitable O—(C₁-C₄)alkyl radicals aremethoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy,sec-butyloxy and tert-butyloxy. . . . .

Examples of 9 or 10-membered bicyclic aromatic heterocyclic group,containing from 1, 2 or 3 heteroatoms independently selected from O, Sor N are indolyl, isoindolyl, quinolyl, isoquinolyl, benzofuranyl,isobenzofuranyl, benzothienyl, isobenzothienyl, quinazolyl, quinoxalyl,phthalazinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl,benzisoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl,benzoxadiazolyl, benzisoxadiazolyl, benzothiadiazolyl andbenzisothiadiazolyl.

Preferred 9 or 10-membered bicyclic aromatic heterocyclic groups arebenzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, isoquinolyland quinolyl. Benzoxazolyl is particularly preferred.

Halo denotes a halogen atom selected from the group consisting offluoro, chloro, bromo and iodo. Preferred halo groups are fluoro andchloro.

In the above compounds of formula (I) and in the intermediates usefulfor their preparation, the following definitions are preferred:

Preferably, R¹ is CONH₂.

Preferably, R⁴ is H or CH₃.

Preferably, A¹ is phenyl optionally substituted with 1, 2 or 3 groupsindependently selected from F, Cl, CF₃, OH, OCH₃, OCF₃ and CH₃. Morepreferably, A¹ is phenyl optionally substituted with 1 or 2 groupsindependently selected from F, Cl, CF₃, OH, OCH₃, OCF₃ and CH₃.

Preferably, A¹ is naphthyl optionally substituted with OH.

Preferably, A¹ is benzoxazolyl.

Preferably, R² and R³ are methyl.

In a preferred embodiment, p is 0.

In another preferred embodiment, p is 1.

In a preferred embodiment, the compound of formula (I) wherein A is agroup of formula

has the below (R) configuration:

In a preferred embodiment, the compounds of formula (I) wherein A is agroup of formula

has the below (S) configuration:

Preferred compounds according to the invention are:

-   5-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanenitrile;-   5-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide;-   5-Methyl-5-[(3R)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanenitrile;-   5-Methyl-5-[(3R)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3S)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3R)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3S)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-Methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-Methyl-5-[(3S)-3-(3-methylphenoxy)pyrrolidin-1-yl]-2,2-diphenylhexanamide;-   5-[(3R)-3-(1,3-Benzoxazol-6-yloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(4-Chlorophenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Bromophenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(3′-Hydroxybiphenyl-4-yl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(3′-Hydroxybiphenyl-3-yl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(6-Hydroxy-2-naphthyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(2-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(4-methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(4-hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(4-trifluromethyl-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(4-Trifluoromethyl-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3R)-3-(4-trifluromethyl-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-chloro-4-methoxy-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3R)-3-(3-chloro-4-methoxy-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Hydroxy-5-methyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(3-Hydroxy-2-methyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2,4-Dichloro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(4,5-Dichloro-2-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(3-Chloro-5-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(3-Chloro-5-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(4-Chloro-2-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(4-Chloro-2-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2-Chloro-3-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2-Chloro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(4-Chloro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2-Chloro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3R)-3-(3-Chloro-2-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[(3R)-3-(3-Chloro-2-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3R)-3-(3-Chloro-2-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(3-Hydroxy-2,5-dimethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(3-Fluoro-5-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(3-Fluoro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3R)-3-(3-Methoxy-5-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[(3R)-3-(3-Methoxy-5-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3R)-3-(3-Hydroxy-5-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(4-Fluoro-3-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2-Fluoro-3-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(4-Fluoro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2-Fluoro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3R)-3-(3-Hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-{(3S)-3-[(3-Bromobenzyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{(3S)-3-[(3′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3S)-3-(Biphenyl-3-ylmethoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-{(3S)-3-[(2′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{(3S)-3-[(4-Bromobenzyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{(3S)-3-[(3′-Hydroxybiphenyl-4-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{(3S)-3-[(3′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(4′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{(3S)-3-[(4′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(2′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(3′-Hydroxybiphenyl-4-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(Biphenyl-3-ylmethoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(4-Fluoro-3-hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Cyano-5-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(2-Cyano-5-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{(3S)-3-[(7-Hydroxy-2-naphthyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(4-Phenylphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-chloro-4-hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-Fluoro-5-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-Fluoro-5-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanamide;-   5-[(3R)-3-(2-Fluoro-3-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(2-Fluoro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(2-Chloro-3-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(2-Chloro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(4-Chloro-3-hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-methoxy-4-chloro-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[(3R)-3-(3-methoxy-4-chloro-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-hydroxy-4-chloro-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-hydroxy-4-cyano-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-methoxy-benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(2-Chloro-3-hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-Methyl-5-(4-phenoxypiperidin-1-yl)-2,2-diphenylhexanenitrile;-   5-{4-[(3-Bromobenzyl)oxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{4-[(3-Hydroxybenzyl)oxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-[4-(Benzyloxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-Methyl-5-(4-phenoxypiperidin-1-yl)-2,2-diphenylhexanamide;-   5-{4-[(3-Bromobenzyl)oxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[4-(Benzyloxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[4-(2,4-Dichloro-5-hydroxy-phenoxy)-piperidin-1-yl]-5-methyl-2,2-diphenylhexanoic    acid amide;-   5-[4-(4-Cyano-2,5-difluoro-phenoxy)-piperidin-1-yl]-5-methyl-2,2-diphenylhexanoic    acid amide;-   5-[4-(3-hydroxyphenoxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[4-(3-hydroxy-2-methylphenoxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{4-[(3′-hydroxybiphenyl-3-yl)methoxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;-   5-{4-[(3′-hydroxybiphenyl-3-yl)methoxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[3-(3-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[3-(3-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[3-(Benzyloxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[3-(Benzyloxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanenitrile;-   5-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanamide,-   5-[3-(4-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile;-   5-[3-(4-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[3-(4-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[3-(2-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{3-(2,4-Dichloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{3-(4,5-Dichloro-2-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[3-(4-Chloro-3-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-{3-(4-Chloro-3-methoxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[3-(3-Hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(2-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(3-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(3-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{3-(3-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[3-(3-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(3-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{3-(3-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[3-(4-Fluoro-2-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(4-Fluoro-2-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{3-(4-Fluoro-2-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-[3-(2,6-Dichloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   4-{1-[3-(3-Methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyronitrile;-   4-{1-[3-(3-Methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   4-{1-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   5-[3-(2-Fluoro-3-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(2-Fluoro-3-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Fluoro-3-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(2-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(4-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   4-{1-[3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   5-[3-(3-Bromo-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-[3-(3-Bromo-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(3-Bromo-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   4-{1-[3-(3-Fluoro-4-methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyronitrile;-   4-{1-[3-(3-Fluoro-4-methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   4-{1-[3-(3-Fluoro-4-hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   5-[3-(3-Chloro-4-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(4-Chloro-2-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(3,5-Dihydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile;-   5-{3-[(4-Hydroxybenzyl)oxy]azetidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile;    and,-   5-[3-(4-Hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide.

More preferred compounds are:

-   5-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide;-   5-Methyl-5-[(3R)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3S)-3-(3-Fluoro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3S)-3-(2-Fluoro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[(3R)-3-(2-Fluoro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(2-Chloro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-Methyl-5-(4-phenoxypiperidin-1-yl)-2,2-diphenylhexanamide;-   5-[4-(3-hydroxyphenoxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanamide;-   5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{3-(3-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{3-(3-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   4-{1-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   5-[3-(2-Fluoro-3-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide; and,-   5-[3-(4-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide.

Most preferred compounds are:

-   5-[(3S)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[(3R)-3-(2-Fluoro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;-   5-{3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{3-(3-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   5-{3-(3-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;-   4-{1-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide;-   5-[3-(2-Fluoro-3-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide;-   5-[3-(2-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide; and,-   5-[3-(4-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic    acid amide.

The invention also relates to processes for the preparation of thecompounds of formula (I) as well as intermediates useful for theirpreparation. In particular, the invention relates to the belowintermediates:

wherein A, p and A¹ are as defined in compounds of formula (I);

wherein A and R¹ are as defined in compounds of formula (I);

wherein R¹, R² and R³ are as defined in compounds of formula (I) and LGis a suitable leaving group such as mesylate or tosylate;

wherein LG is a suitable leaving group such as mesylate or tosylate;and,

wherein R² and R³ are as defined in compounds of formula (I).

Compound of formula (I) may be prepared in a variety of ways. The routesbelow illustrate one such way of preparing these compounds; the skilledperson will appreciate that other routes may be equally as practicable.

Compounds of formula (I) where A is

may be prepared according to the routes disclosed below:

Wherein A is

A¹ and p are as defined above for the compounds of formula (I), and,

PG is a suitable carboxyl-protecting group such as methyl or tert-butyland is typically tert-butyl.

Compound of formula (II) is commercially available.

Compounds of formula (III) are either commercially available or theirpreparation is known from the literature.

Compounds of formula (IV) may be prepared from compounds of formula (II)and (III) by process step (i): compound (II) is treated with compound(III) in the presence of a suitable base such as potassium hydroxide orsodium hydroxide, in a suitable solvent such as methanol, ethanol ortert-butanol, at a temperature between 25° C. and elevated temperaturefor 6-24 hours. Typical conditions comprise of 1.0 equivalent ofcompound (II), 0.05 eq of potassium hydroxide and 1.0 equivalent ofcompound (III) in tert-butanol at a temperature between 25-60° C. for upto 24 hours.

Compounds of formula (V) may be prepared from compounds of formula (IV)by process step (ii). De-protection of compound (IV) may be achievedusing standard methodology as described in “Protecting Groups in OrganicSynthesis” by T. W. Greene and P. Wutz. When PG is tert butyl, typicalconditions comprise of 1.0 equivalent of compound (IV) in the presenceof hydrochloric acid (4M in dioxan), in dichloromethane, at roomtemperature for up to 18 hours.

Compound of formula (VI) may be prepared as described in scheme 2:

Compounds of formula (VIa) are either commercially available or can beprepared as described in scheme 2a

wherein A¹ and p are as defined above for the compounds of formula (I).In some cases, A¹ may be protected with a suitable protecting group. Forexample, when A¹ contains a phenol, it may be protected by a suitablehydroxyl protecting group.

PG′ is a suitable amino protecting group such as tertbutoxycarbonyl(BOC), benzyloxycarbonyl (CBz) and is typically BOC.

X is a suitable functional group such as hydroxy, fluoro, bromo, chloro,iodo, O-mesylate or O-tosylate and is typically hydroxy or bromo.

When PG′ is BOC, compounds of formula (VIII) and (VIIIa) arecommercially available.

Compounds of general formula (IX) are either commercially available,known in the literature, or may be prepared as illustrated in schemes3-5.

wherein A¹ is as defined above for the compounds of formula (I) or maybe optionally protected.

Compounds of formula (IX) where A¹ is as defined for compounds offormula (I), p is 0 and X is OH, may be prepared from compounds offormula (XI) by Baeyer-Villiger oxidation and subsequent hydrolysis(process step (viii)). Typical conditions comprise reaction of 1.0equivalent of compound (XI) with 3.0 equivalents of3-chloroperoxybenzoic acid, in a suitable solvent such asdichloromethane, at room temperature for 18 hours, and subsequenttreatment of this product with a suitable base such as triethylamine, ina suitable solvent such as methanol, at room temperature for 18 hrs.

Compounds of formula (IX) where A¹ contains a suitably protected phenol,p is 0 and X is OH may be prepared from compounds of formula (IXa) whereA¹ contains a phenol, p is 0 and X is OH, by addition of a suitablephenol protecting group such as benzyl, by process step (ix). Typicalconditions comprise reaction of 1.0 equivalent of compound (IXa) with1.0 equivalent of benzyl bromide and 1.0 equivalent of a suitable basesuch as caesium carbonate, in a suitable solvent such asdimethylformamide, at 80° C. for 30 minutes.

Alternatively, compounds of formula (IX) where A¹ contains a suitablyprotected phenol, p is 0 and X is OH may be prepared from compounds offormula (IXa) where A¹ contains a suitably protected phenol, p is 0 andX is OMe, by mono-deprotection using conditions described in “ProtectingGroups in Organic Synthesis” by T. W. Greene and P. Wutz.

Compounds of formula (IX) where A¹ contains a suitably protected phenol,p is 0 and X is F, may be prepared from compounds of formula (IXa) whereA¹ contains a phenol, p is 0 and X is F, by addition of a suitablephenol protecting group such as methyl, by process step six). Typicalconditions comprise reaction of 1.0 equivalent of compound (IXa) with2.0 equivalents of methyl iodide and 1.0 equivalent of a suitable basesuch as potassium carbonate, in a suitable solvent such astetrahydrofuran, at room temperature for 3 hours.

wherein A¹ is as defined above for the compounds of formula (I) or maybe optionally protected.

Compounds of formula (IXa) where p is 1 and X is OH may be prepared fromcompounds of formula (XI) by reduction of the aldehyde with a suitablereducing agent such as sodium borohydride, by process step (xi). Typicalconditions comprise reaction of 1.0 equivalent of compound (XI) with 1.0equivalent of sodium borohydride, in a suitable solvent such as ethanol,at room temperature for 18 hours.

Compounds of formula (XIV) where R⁵ represents a suitable acidprotecting group such as methyl, ethyl or allyl may be prepared fromcompounds of formula (XIII) by addition of a suitable protecting groupsuch as allyl, by process step (x). Typical conditions comprise reactionof 1.0 equivalent of compound (XIII) with 2.0 equivalents of allylbromide and 2.0 equivalents of a suitable base such as potassiumcarbonate, in a suitable solvent such as dimethylformamide, at roomtemperature for 18 hours.

Compounds of formula (IXa) where p is 1 and X is OH may be prepared fromcompounds of formula (XIV) by reduction of the ester with a suitablereducing agent such as lithium aluminium hydride, by process step (xi).Typical conditions comprise reaction of 1.0 equivalent of compound (XIV)with 2.0 equivalent of lithium aluminium hydride, in a suitable solventsuch as tetrahydrofuran, at 0° C. to room temperature over 5 hours.

Compounds of formula (IX) where p is 1 and X is halo may be preparedfrom compounds of formula (IXa) where p is 1 and X is OH, byhalogenation of the primary alcohol using a suitable reagent such asthionyl chloride, dibromotriphenylphosphorane or iodine plus triphenylphosphine, preferably thionyl chloride or dibromotriphenylphosphorane,in a suitable solvent such as dichloromethane or acetonitrile, byprocess step (xii). When X is bromo, Typical conditions comprisereaction of 1.0 equivalent of compound (IXa) with 1.0 equivalent ofdibromotriphenylphosphorane, in a suitable solvent such as acetonitrile,at room temperature for 18 hours. When X is chloro, Typical conditionscomprise reaction of 1.0 equivalent of compound (IXa) with 2.5equivalent of thionyl chloride in dichloromethane at room temperaturefor 10 minutes.

Compounds of formula (X) where p is 0 may be prepared from compounds offormulae (VIII), and (IX) where X is OH and p is 0, by a Mitsunobureaction, between compounds (VIII) and (IX) in the presence of asuitable phosphine such as tri-^(n)butyl phosphine or triphenylphosphine and a suitable azo compound such as diethylazodicarboxylate,diisopropylazodicarboxylate or di-tert-butylazodicarboxylate, in asolvent such as dichloromethane, tetrahydrofuran orN,N-dimethylformamide, at temperatures between 25-115° C., for 1-48hours, by process step (vi). Typical conditions comprise of 1.0equivalent of compound (VIII), 1.0 equivalent of compound (IX) 1.0-1.2equivalents of triphenylphosphine and 1.0-1.2 equivalents ofdi-isopropylazodicarboxylate, in tetrahydrofuran, at 25° C. for up to 18hours. Compounds of formula (Xa) where p is 0 may be prepared fromcompounds of formula (VIIIa) and (IX) using the same conditions.

Compounds of formula (X) where p is 1 may be prepared from compounds offormulae (VIII), and (IX) where X is halo and p is 1, by treatment ofcompound (VIII) with a suitable strong base such sodium hydride orpotassium tert-butoxide followed by quench with compound (IX), in asuitable solvent such as tetrahydrofuran or dimethyl formamide, at atemperature between 0° C. and room temperature, for 1-18 hours, byprocess step (vi). Typical conditions comprise of 1.0 equivalent ofcompound (VIII), 1.0 equivalent of sodium hydride and 1.0 equivalent ofcompound (IX), in tetrahydrofuran, at temperatures between 0-25° C. forup to 18 hours. Compounds of formula (Xa) where p is 1 may be preparedfrom compounds of formula (VIIIa) and (IX) using the same conditions.

Compounds of formula (VI) may be prepared from compounds of formula (X)by process step (vii). De-protection of compound (X) may be achievedusing standard methodology as described in “Protecting Groups in OrganicSynthesis” by T. W. Greene and P. Wutz. When PG′ is BOC, typicalconditions comprise of 1.0 equivalent of compound (X) in the presence ofhydrochloric acid (4M in dioxan), in dichloromethane, at roomtemperature for up to 18 hours.

Compounds of formula (VIa) may be prepared from compounds of formula(Xa) and using the same conditions.

Compounds of formula (VII) may be prepared from compounds of formulae(V) and (VI) or (VIa) by process step (iii), coupling of (V) and (VI) or(VIa) in the presence of a suitable coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, optionally inthe presence of a catalyst such as 1-hydroxybenzotriazole hydrate or1-hydroxy-7-azabenzotriazole, and optionally in the presence of atertiary amine base such as N-methylmorpholine, triethylamine orN,N-diisopropylethylamine, in a suitable solvent such asN,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide, underambient conditions for 1-48 hours. Typical conditions comprise of 1.0equivalent of compound (V), 1.0 equivalent of compound (VI) or (VIa) and1.0-1.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, 1.0-1.2 equivalents of 1-hydroxybenzotriazole hydrate and1.0-1.2 equivalents triethylamine in dichloromethane, at roomtemperature for 18 hours.

Compounds of formula (Ia) may be prepared from compounds of formula(VII) by process step (iv). Compound (Ia) may be prepared in analogy tothe methods of Denton and Wood (Synlett, 1999, 1, 55); Compound (VII) istypically pre-activated with a suitable Lewis acid such as titaniumchloride or zirconium chloride then treated with an excess of a suitableorganometallic reagent such as MeMgCl or MeMgBr, in a suitable solventsuch as tetrahydrofuran or diethyl ether, at a temperature between −78°C. to 25° C., for 1-18 hours. Typical conditions comprise of 1.0equivalent of compound (VII), 2 equivalents of zirconium chloride and9.0 equivalents of MeMgCl in tetrahydrofuran, at −30° C. for 4-8 hours.

Compounds of formula (Ib) may be prepared from compounds of formula (Ia)by hydrolysis of compound (Ia) with an excess of potassium hydroxide in3-methyl-3-pentanol, at elevated temperature for up to 24 hours (processstep (v)). Typical conditions comprise of 1.0 equivalent of compound(Ia) and 20 equivalents of potassium hydroxide in 3-methyl-3-pentanol atelevated temperature for up to 24 hours.

In a further embodiment, when p is 1, compounds of formula (I) can befurther functionalised to provide compounds of formula (Ic), asdescribed in scheme 6

wherein A is

R² and R³ are methyl.

Compounds of formula (XV) may be prepared from compounds of formula (I)where p is 1, by process step (xiii). When R¹ is CN, cleavage of thebenzyl ether group is typically achieved by treatment of compound (I)with an excess of iron (III) chloride, in a suitable solvent such asdichloromethane, under ambient conditions for 1-8 hours to providecompounds of formula (XV). When R¹ is CONH₂ treatment of compound (I)with hydrogen gas, in the presence of a suitable hydrogenation catalystsuch as 20% Pd(OH)₂ or 10% Pd/C, optionally in the presence of asuitable acid such as hydrochloric acid, in a suitable solvent such asmethanol, ethanol or tetrahydrofuran, at elevated temperature for 1-18hours, provides compounds of formula (XV).

Compounds of formula (Ic) where p is 0 may be prepared from compounds offormula (XV) and compounds of formula (IX) where p is 0 and X is OH byprocess step (xiv)—using the conditions disclosed for step (vi).

Compounds of formula (Ic) where p is 0 may be prepared from compounds offormula (XV) and a compound of formula (IX) where p is 0 and X is F, byprocess step (xiv)—treatment of compound (XV) with a suitable strongbase such sodium hydride or potassium tert-butoxide followed by quenchwith compound (IX), in a suitable solvent such as tetrahydrofuran orN,N-dimethylformamide, at a temperature between 0° C. and elevatedtemperature, for 1-96 hours. Typical conditions comprise of 1.0equivalent of compound (XV), 1.0 to 2.0 equivalents of sodium hydrideand 1.0 equivalent of compound (IX), in N,N-dimethylformamide, attemperatures between 0-60° C. for 18-96 hours.

Compounds of formula (Ic) where p is 1 may be prepared from compounds offormula (XV) and a compound of formula (IX) where p is 1 and X is Cl,Br, I, O-mesylate or O-tosylate by process step (xiv), treatment ofcompound (XV) with a suitable strong base such sodium hydride orpotassium tert-butoxide followed by quench with compound (IX), in asuitable solvent such as tetrahydrofuran or N,N-dimethylformamide, at atemperature between 0° C. and elevated temperature, for 1-96 hours.Typical conditions comprise of 1.0 equivalent of compound (XV), 1.0 to2.0 equivalents of sodium hydride and 1.0 equivalent of compound (IX),in N,N-dimethylformamide, at temperatures between 0-60° C. for 18-96hours.

In a further embodiment, compounds of formula (I) can be furtherfunctionalised to provide compounds of formula (Id), as described inscheme 7:

wherein A is

Compounds of formula (Id) where A¹ represents phenyl substituted withphenyl optionally substituted with OH, may be prepared from compounds offormula (i) where A¹ is phenyl substituted with Cl, Br or I, by processstep (xv), Suzuki coupling reaction with compound (XXX) in a suitablesolvent, such as 1,4-dioxane or tetrahydrofuran, in the presence ofwater, a suitable base such as sodium carbonate or caesium carbonate,and a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride ortetrakis(triphenyl phosphine)palladium(0). Suzuki coupling reactions canbe carried out as described in the literature: Suzuki, A. Pure & Appl.Chem. 1985, 57, 1749 and references contained within; Angew. Chem. Int.Ed. 2002, 41, 4176 and references contained within. Typical conditionscomprise 1.0 equivalent of compound (I), 2.0 equivalents of compound(XXX), 2.0 equivalents of sodium carbonate and 0.05 equivalents ofpalladium catalyst in tetrahydrofuran and water, at elevated temperaturefor up to 16 hours.

Compound (XVI) is either commercially available or may be prepared bymethods described in the literature.

Compounds of formula (Ic) and (Id) where R¹ is CONH₂ may also beprepared from compounds of formula (Ic) and (Id) where R¹ is CN, byhydrolysis with an excess of potassium hydroxide in 3-methyl-3-pentanol,at elevated temperature for up to 24 hours. Typical conditions compriseof 1.0 equivalent of compound (Ic) or (Id) where R¹ is CN and 20equivalents of potassium hydroxide in 3-methyl-3-pentanol at reflux forup to 24 hours.

Compounds of formula (I) where A is

may be prepared according to the routes disclosed below:

wherein LG represents a suitable leaving group such as mesylate ortosylate and is preferably mesylate.

Compounds of formula (XVI) may be prepared as described in WO2003037327,page 83. PG′″ represents a protecting group such as tert-butoxycarbonylor benzyloxycarbonyl and is preferably tert-butoxycarbonyl.Alternatively, compounds of formula (XVI) may be prepared according tothe following process:

Compounds of formula (XVIc) are commercially available or known in theliterature.

Compounds of formula (XVIb) may be prepared from compounds of formula(XVIc) by reaction of compounds (XVIc) with chlorosulfonyl isocyanate,formic acid and pyridine, in a suitable solvent such as dichloromethane,at low temperature for 2 hours (process step (xxi)). Typical conditionscomprise 1.0 equivalent of compound (XVIc), 1.5 equivalents ofchlorosulfonyl isocyanate, 1.5 equivalents of formic acid and 1.5equivalents of pyridine in dichloromethane, at low temperature for 2hours.

Compounds of formula (XVIa) may be prepared from compounds of formula(XVIb) by reaction of compounds (XVIb) with magnesium oxide, iodobenzenediacetate and rhodium acetate dimer in a suitable solvent such asdichloromethane at room temperature for up to 24 hours (process step(xxii)). Typical conditions comprise reaction of 1.0 equivalent ofcompound (XVIb), 2.3 equivalent of magnesium dioxide, 1.1 equivalent ofiodobenzene diacetate and 0.02 equivalent of rhodium acetate dimer indichloromethane at room temperature for 18 hours.

Compounds of formula (XVI) may be prepared from compounds of formula(XVIa) by incorporation of a suitable protecting group such astert-butoxycarbonyl or benzyloxycarbonyl, preferablytert-butoxycarbonyl, using conditions described in “Protecting Groups inOrganic Synthesis” by T. W. Greene and P. Wutz. Typical conditionscomprise reaction of 1.0 equivalent of compound (XVIa), 1.2 equivalentsof di-tert-butyl dicarbonate, 2.0 equivalents of triethylamine and 0.2equivalents of 4-dimethylaminopyridine in dichloromethane, at roomtemperature for 3 hours.

Compounds of formula (XVII) may be prepared from compounds of formula(II) and compounds of formula (XVI) by process step (xvi)—

-   -   1) Reaction of compounds (II) and (XVI) in the presence of a        strong base such as potassium tert butoxide or sodium hydride,        in a suitable solvent such as N,N-dimethylformamide or        dimethylsulfoxide, under ambient conditions or at elevated        temperature for up to 18 hours.    -   2) Removal of the protecting group (when used) using suitable        conditions such as 4N hydrochloric acid in dioxan or        trifluoroacetic acid or hydrogenation in the presence of        catalytic palladium, as described in “Protecting Groups in        Organic Synthesis” by T. W. Greene and P. Wutz.

Typical conditions comprise of 1.2 equivalents of compound (II), 1.0equivalent of compound (XVI) and 1.2 equivalents of potassium tertbutoxide in N,N-dimethylformamide, under ambient conditions for up to 18hours, followed by treatment with 4N hydrochloric acid in dioxane.

Compounds of formula (XVIII) are commercially available.

Compounds of formula (XIX) may be prepared from compounds of formula(XVII) and (XVIII) by process step (xvii)—heterocycle formation can beachieved by nucleophilic addition of compound (XVIII) by compound (XVII)followed by in situ ring closure, in a suitable solvent such as methanolor ethanol, at elevated temperature for up to 48 hours. Typicalconditions comprise of 1.0 equivalent of compound (XVII) and 1.1equivalents of compound (XVIII) in methanol, at elevated temperature forup to 48 hours.

Compounds of formula (XX) may be prepared from compounds of formula(XIX) by process step (xviii) introduction of a suitable leaving group(LG), such as mesylate or tosylate groups by reaction of compound (XIX)with mesyl chloride/anhydride or tosyl chloride, in the presence of asuitable base such as Hünig's base, triethylamine or pyridine,optionally in a suitable solvent such as dichloromethane or diethylether, at low temperature for 1-2 hours. Typical conditions comprise of1.0 equivalent of compound (XIX) and 3 equivalents of mesyl chloride inpyridine at low temperature for up to 1-2 hours.

Compounds of general formula (XXI) are either commercially available orare known in the literature. Compounds of formula (XXI) containing aphenol group may be protected by addition of a suitable phenolprotecting group such as allyl. Typical conditions comprise reaction of1.0 equivalent of compound (XXI) containing a phenol with 1.0 equivalentof allyl bromide and 1.0 equivalent of a suitable base such as potassiumcarbonate, in a suitable solvent such as dimethylformamide, at roomtemperature for 18 hours.

Alternatively, compounds of formula (XXI) may be prepared bymono-deprotection of a bis-protected phenol using conditions describedin “Protecting Groups in Organic Synthesis” by T. W. Greene and P. Wutz.

Compounds of formula (Ie) can be prepared from compounds of generalformula (XX) and (XXI) by treatment of compound (XXI) with a suitablebase such caesium carbonate or sodium carbonate followed by quench withcompound (XX), in a suitable solvent such as N,N-dimethylformamide ordimethylsulfoxide, at elevated temperature for up to 18 hours (processstep (xix)). Typical conditions comprise of 1.0 equivalent of compound(XX), 3.0 equivalents of caesium carbonate and 3.0 equivalent ofcompound (XXI), in N,N-dimethylformamide, at elevated temperature for upto 18 hours.

In a further embodiment, compounds of formula (If) may be prepared fromcompounds of formula (Ie) by hydrolysis of compound (Ie) with an excessof potassium hydroxide in 3-methyl-3-pentanol, at elevated temperaturefor up to 24 hours (process step (xx)). Typical conditions comprise of1.0 equivalent of compound (Ie) and 20 equivalents of potassiumhydroxide in 3-methyl-3-pentanol at elevated temperature for up to 24hours.

Alternatively compounds of formula (I) where A is

and R² and R³ are methyl may be prepared as described in scheme 9.

wherein LG represents a suitable leaving group such as mesylate ortosylate and is preferably mesylate.

Compounds of general formula (V) may be prepared as described inWO97/24325.

Compounds of formula (XXII) may be prepared from compounds of generalformula (V) by process step (xxiv): carboxylic acid (V) may be treatedwith a suitable chlorinating agent such as thionyl chloride or oxalylchloride, in a suitable solvent such as N,N-dimethylformamide,acetonitrile or dichloromethane, under ambient conditions for up to 8hours. Typical conditions comprise of 1.0 equivalent of compound (V) and2 equivalents of oxalyl chloride in N,N-dimethylformamide, at roomtemperature for 2 hours.

Compounds of formula (XXIII) may be prepared as described in J. Org.Chem. 1991, 56, 6729-30.

Compounds of general formula (XXIV) may be prepared from compounds ofgeneral formula (XXII) and (XXIII) by process step (xxv): compound(XXII) undergoes nucleophilic substitution with compound (XXIII), in thepresence of a tertiary amine base such as N-methylmorpholine,triethylamine or N,N-diisopropylethylamine, in a suitable solvent suchas N,N-dimethylformamide, tetrahydrofuran or dichloromethane, at lowtemperature for 1-8 hours. Typical conditions comprise of 1 equivalentof compound (XXII), 1 equivalent of compound (XXIII) and 3 equivalentsof triethylamine in dichloromethane, at low temperature for 1 hour.

Compounds of general formula (XXV) may be prepared from compounds ofgeneral formulae (XXIV) and (XXI) by process step (xxvi) using theconditions described for step (xix) in scheme 8.

Compound of formula (Ie) may be prepared from compounds of formula (XXV)using the conditions disclosed for step (iv) of scheme 1.

Compounds of formula (If) may be prepared from compounds of formula (Ie)using the conditions disclosed for step (xx) of scheme 8.

Alternatively, compounds of formula (I) may be prepared as disclosed inscheme 1, using an intermediate of formula (VIb)

which is commercially available or known in the literature.

Typical conditions for step (iii) comprise of 1.0 equivalent of compound(V), 1.2 equivalent of compound (VIb), 1.0-1.2 equivalents of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.0-1.2equivalents of 1-hydroxybenzotriazole hydrate and 2.5 equivalents ofN,N-diisopropylethylamine in dichloromethane, at room temperature for 18hours.

Alternatively, a compound of formula (Ie) wherein p is 1 may be preparedas described in scheme 10:

wherein p is 1 and Hal represents halo and is typically chloro or bromo,preferably chloro.

Compound of formula (XXVI) may be prepared as disclosed in scheme 5.

Compounds of general formula (Ie) may be prepared from compounds ofgeneral formulae (XIX) and (XXVI) by treatment of compound (XIX) with asuitable strong base such sodium hydride or potassium tert-butoxidefollowed by quench with compound (XXVI), in a suitable solvent such astetrahydrofuran, at a temperature between 0° C. and room temperature,for 1-8 hours. Typical conditions comprise of 1.0 equivalent of compound(XIX), 1.2 equivalents of sodium hydride and 1.5 equivalents of compound(XXVI), in tetrahydrofuran, at temperatures between 0-25° C. for up to1-2 hours.

Alternatively, compounds of formula (If) may be prepared as described inscheme 11.

wherein Hal represents halo and is typically chloro or bromo, preferablychloro.

Compounds of formula (XXVII) are prepared from compounds of formula(If), where A¹ represents phenyl and p=1, by removal of the benzyl groupusing standard hydrogenation conditions as described in “ProtectingGroups in Organic Synthesis” by T. W. Greene and P. Wutz.

Compounds of formula (If) are prepared from compounds of formula (XXVII)and compounds of formula (XXVI), using the conditions disclosed in step(xxix).

Alternatively, compounds of formula (If) may be prepared as described inscheme 12.

wherein LG represents a suitable leaving group such as mesylate ortosylate and is preferably mesylate.

Compounds of formula (XXVIII) can be prepared from compounds of formula(XXVII) by process step (xviii), as described in scheme 8.

Compounds of formula (If) can be prepared from compounds of formula(XXVIII) and compounds of formula (XXI) by process step (xix), asdescribed in scheme 8.

Alternatively, compounds of formula (XIX) may be prepared as describedin scheme 13.

wherein R² and R³ represent methyl.

Compound of formula (XXXI) is commercially available.

Compound of formula (XXXII) can be prepared from compound of formula (V)and compound of formula (XXXI) using the conditions disclosed for step(iii) of scheme 1.

Compounds of formula (XIX) can be prepared from compound of formula(XXXII) using the conditions disclosed for step (iv) of scheme 1.

When A¹ contains a suitably protected phenol, compounds of formula (I)are deprotected to provide the corresponding phenol. Suitable protectinggroups (PG″) include methyl, benzyl, allyl and tert-butyldimethylsilyl(TBDMS). De-protection may be achieved using standard methodology asdescribed in “Protecting Groups in Organic Synthesis” by T. W. Greeneand P. Wutz.

When PG″ is methyl, Typical conditions of this procedure comprise of 1.0equivalent of protected compound of formula (I) and 1-4 equivalents of1M boron tribromide in dichloromethane, in a suitable solvent such asdichloromethane, at ambient temperature for 1-18 hours.

When PG″ is allyl, Typical conditions of this procedure comprise of 1.0equivalent of protected compound of formula (I) and 20 equivalents ofpotassium hydroxide in 3-methyl-3-pentanol at reflux for 1-24 hrs,followed by isolation of the residue and treatment with hydrochloricacid (4M in dioxan), in water, at 60° C. for 20 mins. Alternativeconditions of this procedure comprise of 1.0 equivalent of protectedcompound of formula (I), 6 equivalents of sodium borohydride and 0.1equivalents of tetrakis(triphenylphosphine)palladium(0) intetrahydrofuran at elevated temperature for 30 minutes.

When PG″ is TBDMS, Typical conditions of this procedure comprise of 1.0equivalent of protected compound of formula (I) and 10 equivalents ofammonium fluoride in methanol and water at 50° C. for 18-24 hrs.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

-   (i) by reacting the compound of formula (I) with the desired acid or    base;-   (ii) by removing an acid- or base-labile protecting group from a    suitable precursor of the compound of formula (I) or by ring-opening    a suitable cyclic precursor, for example, a lactone or lactam, using    the desired acid or base; or-   (iii) by converting one salt of the compound of formula (I) to    another by reaction with an appropriate acid or base or by means of    a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterised by a phase change, typically first order (‘meltingpoint’).

The compounds of the invention may also exist in unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-componentcomplexes (other than salts and solvates) wherein the drug and at leastone other component are present in stoichiometric or non-stoichiometricamounts. Complexes of this type include clathrates (drug-host inclusioncomplexes) and co-crystals. The latter are typically defined ascrystalline complexes of neutral molecular constituents which are boundtogether through non-covalent interactions, but could also be a complexof a neutral molecule with a salt. Co-crystals may be prepared by meltcrystallisation, by recrystallisation from solvents, or by physicallygrinding the components together—see Chem Commun, 17, 1889-1896, by O.Almarsson and M. J. Zaworotko (2004). For a general review ofmulti-component complexes, see J Pharm Sci, 64 (8), 1269-1288, byHaleblian (August 1975).

The compounds of the invention may also exist in a mesomorphic state(mesophase or liquid crystal) when subjected to suitable conditions. Themesomorphic state is intermediate between the true crystalline state andthe true liquid state (either melt or solution). Mesomorphism arising asthe result of a change in temperature is described as ‘thermotropic’ andthat resulting from the addition of a second component, such as water oranother solvent, is described as ‘lyotropic’. Compounds that have thepotential to form lyotropic mesophases are described as ‘amphiphilic’and consist of molecules which possess an ionic (such as —COO⁻Na⁺,—COO⁻K⁺, or —SO₃ ⁻Na⁺) or non-ionic (such as —N⁻N⁺(CH₃)₃) polar headgroup. For more information, see Crystals and the Polarizing Microscopeby N. H. Hartshorne and A. Stuart, 4^(th) Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates, multi-component complexes and liquidcrystals thereof and to solvates, multi-component complexes and liquidcrystals of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula (I).

As indicated, so-called ‘prodrugs’ of the compounds of formula (I) arealso within the scope of the invention. Thus certain derivatives ofcompounds of formula (I) which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of formula (I) having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found inPro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,Pergamon Press, 1987 (Ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include

-   (i) where the compound of formula (I) contains a carboxylic acid    functionality (—COOH), an ester thereof, for example, a compound    wherein the hydrogen of the carboxylic acid functionality of the    compound of formula (I) is replaced by (C₁-C₈)alkyl;-   (ii) where the compound of formula (I) contains an alcohol    functionality (—OH), an ether thereof, for example, a compound    wherein the hydrogen of the alcohol functionality of the compound of    formula (I) is replaced by (C₁-C₆)alkanoyloxymethyl; and-   (iii) where the compound of formula (I) contains a primary or    secondary amino functionality (—NH₂ or —NHR where R≠H), an amide    thereof, for example, a compound wherein, as the case may be, one or    both hydrogens of the amino functionality of the compound of    formula (I) is/are replaced by (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of formula (I) may themselves act asprodrugs of other compounds of formula I.

Also included within the scope of the invention are metabolites ofcompounds of formula I, that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include

-   (i) where the compound of formula (I) contains a methyl group, an    hydroxymethyl derivative thereof (—CH₃->—CH₂OH):-   (ii) where the compound of formula (I) contains an alkoxy group, an    hydroxy derivative thereof (—OR->—OH);-   (iii) where the compound of formula (I) contains a tertiary amino    group, a secondary amino derivative thereof (—NR¹R²->—NHR¹ or    —NHR²);-   (iv) where the compound of formula (I) contains a secondary amino    group, a primary derivative thereof (—NHR¹->—NH₂);-   (v) where the compound of formula (i) contains a phenyl moiety, a    phenol derivative thereof (—Ph->—PhOH); and-   (vi) where the compound of formula (I) contains an amide group, a    carboxylic acid derivative thereof (—CONH₂->COOH).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (I)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of formula (I)containing, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula I, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are intermediate compounds offormula II as hereinbefore defined, all salts, solvates and complexesthereof and all solvates and complexes of salts thereof as definedhereinbefore for compounds of formula I. The invention includes allpolymorphs of the aforementioned species and crystal habits thereof.

When preparing compounds of formula (I) in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe form of compound of formula II which provides the best combinationof features for this purpose. Such features include the melting point,solubility, processability and yield of the intermediate form and theresulting ease with which the product may be purified on isolation.

The compounds of formula (I) should be assessed for theirbiopharmaceutical properties, such as solubility and solution stability(across pH), permeability, etc., in order to select the most appropriatedosage form and route of administration for treatment of the proposedindication.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof).

Generally, they will be administered as a formulation in associationwith one or more pharmaceutically acceptable excipients. The term‘excipient’ is used herein to describe any ingredient other than thecompound(s) of the invention. The choice of excipient will to a largeextent depend on factors such as the particular mode of administration,the effect of the excipient on solubility and stability, and the natureof the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in Remington'sPharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid, semi-solidand liquid systems such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, or powders; lozenges (includingliquid-filled); chews; gels; fast dispersing dosage forms; films;ovules; sprays; and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsules(made, for example, from gelatin or hydroxypropylmethylcellulose) andtypically comprise a carrier, for example, water, ethanol, polyethyleneglycol, propylene glycol, methylcellulose, or a suitable oil, and one ormore emulsifying agents and/or suspending agents. Liquid formulationsmay also be prepared by the reconstitution of a solid, for example, froma sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate; zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight %to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound offormula I, a film-forming polymer, a binder, a solvent, a humectant, aplasticiser, a stabiliser or emulsifier, a viscosity-modifying agent anda solvent. Some components of the formulation may perform more than onefunction.

The compound of formula (I) may be water-soluble or insoluble. Awater-soluble compound typically comprises from 1 weight % to 80 weight%, more typically from 20 weight % to 50 weight %, of the solutes. Lesssoluble compounds may comprise a greater proportion of the composition,typically up to 88 weight % of the solutes. Alternatively, the compoundof formula (I) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Pharmaceutical Technology On-line,25(2), 1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular, intrasynovial andsubcutaneous. Suitable devices for parenteral administration includeneedle (including microneedle) injectors, needle-free injectors andinfusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophitisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as asuspension or as a solid, semi-solid, or thixotropic liquid foradministration as an implanted depot providing modified release of theactive compound. Examples of such formulations include drug-coatedstents and semi-solids and suspensions comprising drug-loadedpoly(dl-lactic-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically,(intra)dermally, or transdermally to the skin or mucosa. Typicalformulations for this purpose include gels, hydrogels, lotions,solutions, creams, ointments, dusting powders, dressings, foams, films,skin patches, wafers, implants, sponges, fibres, bandages andmicroemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, J Pharm Sci, 88 (10),955-958, by Finnin and Morgan (October 1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler, as an aerosol spray froma pressurised container, pump, spray, atomiser (preferably an atomiserusing electrohydrodynamics to produce a fine mist), or nebuliser, withor without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or asnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of formula I, propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 0.001 mg to 10 mg of the compoundof formula (I). The overall daily dose will typically be in the range0.001 mg to 40 mg which may be administered in a single dose or, moreusually, as divided doses throughout the day.

The compounds of formula (I) are particularly suitable for anadministration by inhalation

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments, gels,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.001 mg to 5000 mgdepending, of course, on the mode of administration. For example, oraladministration may require a total daily dose of from 0.1 mg to 1000 mg,while an intravenous dose may only require from 0.001 mg to 100 mg. Thetotal daily dose may be administered in single or divided doses and may,at the physician's discretion, fall outside of the typical range givenherein.

These dosages are based on an average human subject having a weight ofabout 60 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

The compounds of formula (I) have the ability to interact withmuscarinic receptors and thereby have a wide range of therapeuticapplications, as described further below, because of the essential rolewhich muscarinic receptors play in the physiology of all mammals.

Thus the invention relates to the use of the compounds of formula (I)for the manufacture of a medicament for the treatment or the preventionof diseases, disorders, and conditions in which the M3 receptor isinvolved. The invention further relates to a method of treatment of amammal, including a human being, with a M3 antagonist including treatingsaid mammal with an effective amount of a compound of the formula (I) orwith a pharmaceutically acceptable salt, derived form or compositionthereof.

Therefore, a further aspect of the present invention relates to thecompounds of formula (I), or pharmaceutically acceptable salts, derivedforms or compositions thereof, for use in the treatment of diseases,disorders, and conditions in which muscarinic receptors are involved.Examples of such diseases, disorders, and conditions are InflammatoryBowel Disease, Irritable Bowel Disease, diverticular disease, motionsickness, gastric ulcers, radiological examination of the bowel,symptomatic treatment of BPH (benign prostatic hyperplasia), NSAIDinduced gastric ulceration, urinary Incontinence (including urgency,frequency, urge incontinence, overactive bladder, nocturia and Lowerurinary tract symptoms), cycloplegia, mydriatics, parkinsons disease.

More specifically, the present invention also concerns the compounds offormula (I), or pharmaceutically acceptable salts, derived forms orcompositions thereof, for use in the treatment of diseases, disorders,and conditions selected from the group consisting of:

-   -   chronic or acute bronchoconstriction, chronic bronchitis, small        airways obstruction, and emphysema,    -   obstructive or inflammatory airways diseases of whatever type,        etiology, or pathogenesis, in particular an obstructive or        inflammatory airways disease that is a member selected from the        group consisting of chronic eosinophilic pneumonia, chronic        obstructive pulmonary disease (COPD), COPD that includes chronic        bronchitis, pulmonary emphysema or dyspnea associated or not        associated with COPD, COPD that is characterized by        irreversible, progressive airways obstruction, adult respiratory        distress syndrome (ARDS), exacerbation of airways        hyper-reactivity consequent to other drug therapy and airways        disease that is associated with pulmonary hypertension,    -   bronchitis of whatever type, etiology, or pathogenesis, in        particular bronchitis that is a member selected from the group        consisting of acute bronchitis, acute laryngotracheal        bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus        bronchitis, dry bronchitis, infectious asthmatic bronchitis,        productive bronchitis, staphylococcus or streptococcal        bronchitis and vesicular bronchitis,    -   asthma of whatever type, etiology, or pathogenesis, in        particular asthma that is a member selected from the group        consisting of atopic asthma, non-atopic asthma, allergic asthma,        atopic bronchial IgE-mediated asthma, bronchial asthma,        essential asthma, true asthma, intrinsic asthma caused by        pathophysiologic disturbances, extrinsic asthma caused by        environmental factors, essential asthma of unknown or inapparent        cause, non-atopic asthma, bronchitis asthma, emphysematous        asthma, exercise-induced asthma, allergen induced asthma, cold        air induced asthma, occupational asthma, infective asthma caused        by bacterial, fungal, protozoal, or viral infection,        non-allergic asthma, incipient asthma, wheezy infant syndrome        and bronchiolitis,    -   acute lung injury,    -   bronchiectasis of whatever type, etiology, or pathogenesis, in        particular bronchiectasis that is a member selected from the        group consisting of cylindric bronchiectasis, sacculated        bronchiectasis, fusiform bronchiectasis, capillary        bronchiectasis, cystic bronchiectasis, dry bronchiectasis and        follicular bronchiectasis.

More specifically, the present invention also concerns the compounds offormula (I), or pharmaceutically acceptable salts, derived forms orcompositions thereof, for use in the treatment of COPD or asthma.

Suitable examples of other therapeutic agents which may be used incombination with the compound(s) of formula (I), or pharmaceuticallyacceptable salts, derived forms or compositions thereof, include, butare by no means limited to:

-   (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating    protein (FLAP) antagonists,-   (b) Leukotriene antagonists (LTRAs) including antagonists of LTB₄,    LTC₄, LTD₄, and LTE₄,-   (c) Histamine receptor antagonists including H1 and H3 antagonists,-   (d) α₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic    agents for decongestant use,-   (e) short or long acting β₂ agonists,-   (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,-   (g) Theophylline,-   (h) Sodium cromoglycate,-   (i) COX inhibitors both non-selective and selective COX-1 or COX-2    inhibitors (NSAIDs),-   (j) Oral and inhaled glucocorticosteroids,-   (k) Monoclonal antibodies active against endogenous inflammatory    entities,-   (l) Anti-tumor necrosis factor (anti-TNF-α) agents,-   (m) Adhesion molecule inhibitors including VLA-4 antagonists,-   (n) Kinin-B₁- and B₂-receptor antagonists,-   (o) Immunosuppressive agents,-   (p) Inhibitors of matrix metalloproteases (MMPs),-   (q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,-   (r) Elastase inhibitors,-   (s) Adenosine A2a receptor agonists,-   (t) Inhibitors of urokinase,-   (u) Compounds that act on dopamine receptors, e.g. D2 agonists,-   (v) Modulators of the NFκB pathway, e.g. IKK inhibitors,-   (w) modulators of cytokine signalling pathyways such as p38 MAP    kinase or syk kinase,-   (x) Agents that can be classed as mucolytics or anti-tussive,-   (y) Antibiotics,-   (z) HDAC inhibitors, and,-   (aa) PI3 kinase inhibitors.-   (bb) CXCR2 antagonists.    -   According to the present invention, combination of the compounds        of formula (I) with:    -   H3 antagonists,    -   β₂ agonists,    -   PDE4 inhibitors,    -   steroids, especially glucocorticosteroids,    -   Adenosine A2a receptor agonists,    -   Modulators of cytokine signalling pathyways such as p38 MAP        kinase or syk kinase, or,    -   Leukotriene antagonists (LTRAs) including antagonists of LTB₄,        LTC₄, LTD₄, and LTE₄, are preferred.    -   According to the present invention, combination of the compounds        of formula (I) with        -   glucocorticosteroids, in particular inhaled            glucocorticosteroids with reduced systemic side effects,            including prednisone, prednisolone, flunisolide,            triamcinolone acetonide, beclomethasone dipropionate,            budesonide, fluticasone propionate, ciclesonide, and            mometasone furoate, or        -   β2 agonists including in particular salbutamol, terbutaline,            bambuterol, fenoterol, salmeterol, formoterol, tulobuterol            and their salts.            are further preferred.

The following examples illustrate the preparation of the compounds ofthe formula (I):

PREPARATION 1 Tert-butyl 4-Cyano-4,4-Diphenylbutanoate

A suspension of diphenylacetonitrile (38.6 g, 200 mmol) in tert-butanol(200 ml) was warmed to 60° C. for 30 minutes. The resulting solution wascooled to 50° C. and a solution of potassium hydroxide (0.6 g, 10.69mmol) in methanol (2 mL) was added. tert-Butyl acrylate (30 mL, 200mmol) was then added dropwise and the mixture was stirred at 50° C. for2 hours and at room temperature for 18 hours. Further potassiumhydroxide (0.6 g, 10.69 mmol) was added and the mixture was re-warmed to50° C. for 3 hours. The reaction mixture was then concentrated in vacuoand the residue was diluted with diethyl ether (300 mL), washed withwater (200 mL), dried over sodium sulfate and concentrated in vacuo toafford the title compound as a white solid in 90% yield, 57.95 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.41(s, 9H), 2.29(t, 2H), 2.72(t, 2H),7.29-7.33(m, 1H), 1H), 7.36-7.42(m, 9H); LRMS APCI m/z 322 [M+H]⁺

PREPARATION 2 4-Cyano-4,4-Diphenylbutanoic Acid

A mixture of the product of preparation 1 (57.5 g, 179.13 mmol) inhydrochloric acid (4N in dioxan, 500 mL) was stirred at room temperaturefor 18 hours. The reaction mixture was concentrated in vacuo and theresidue was treated with warm diisopropyl ether (150 mL) then cooled toroom temperature. The resulting solid was filtered off, washing throughwith diisopropyl ether (2×30 mL), and dried under vacuum to afford thetitle compound as crystalline white solid in 77% yield, 36.45 g.

¹HNMR(400 MHz, CD₃OD) δ: 2.35(t, 2H), 2.76(t, 2H), 7.30-7.44(m, 10H);LRMS APCI m/z 266 [M+H]⁺

PREPARATION 3 Tert-Butyl (3S)-3-Phenoxypyrrolidine-1-Carboxylate

Di-isopropylazodicarboxylate (5.7 mL, 29.38 mmol) was added to anice-cooled solution of (R)-(−)-N-boc-3-pyrrolidinol (5 g, 26.71 mmol),phenol (2.51 g, 26.71 mmol) and triphenyl phosphine (7.71 g, 29.38 mmol)in tetrahydrofuran (70 mL) and the mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then concentrated invacuo and the residue was twice triturated with diethyl ether andfiltered. The filtrate was washed with 1N sodium hydroxide solution (20mL), dried over sodium sulfate and concentrated in vacuo. Purificationof the residue by column chromatography on silica gel, eluting withpentane:ethyl acetate, 90:10 to 83:17, afforded the title compound as acolourless oil in 75% yield, 5.27 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.45(m, 9H), 2.10-2.16(m, 2H), 3.40-3.59(m,4H), 4.95-4.97(m, 1H), 6.88-6.95(m, 3H), 7.24-7.28(m, 2H)

PREPARATION 4 Tert-Butyl(3S)-3-(3-Methoxyphenoxy)Pyrrolidine-1-Carboxylate

The title compound was prepared from (R)-(−)-N-boc-3-pyrrolidinol and3-methoxyphenol, using the same method as that described for preparation3, as a gum in 81% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.45(m, 9H), 2.14(bs, 2H), 3.40-3.58(m, 4H),3.75(s, 3H), 4.95(m, 1H), 6.45-6.54(m, 3H), 7.14-7.18(m, 1H)

PREPARATION 5 Tert-Butyl (3S)-3-(Benzyloxy)Pyrrolidine-1-Carboxylate

Sodium hydride (60% dispersion in mineral oil, 2.13 g, 53.41 mmol) wasadded portionwise to an ice-cooled solution of(S)-(−)-N-boc-3-pyrrolidinol (10 g, 53.41 mmol) in tetrahydrofuran (100mL) and the mixture was stirred at 0° C. for 1 hour. Benzyl bromide (6.4mL, 53.41 mmol) and tetrahydrofuran (50 mL) were added and the mixturewas stirred for 6 hours allowing the temperature to rise to 25° C. Thereaction mixture was then slowly diluted with water (50 mL),concentrated in vacuo and the aqueous residue was extracted with ethylacetate (3×70 mL). The combined organic solution was washed with brine(30 mL), dried over sodium sulfate and concentrated in vacuo to give anorange oil. This oil was purified by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to90:10:1. The appropriate fractions were evaporated under reducedpressure and the residue was further purified by column chromatographyon silica gel, eluting with pentane:ethyl acetate, 66:33, to afford thetitle compound as a colourless oil in 74% yield, 10.93 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.45(s, 9H), 1.91-2.00(m, 1H), 2.02-2.08(m,1H), 3.35-3.44(m, 4H), 4.13-4.17(m, 1H), 4.51-4.52(m, 2H), 7.24-7.29(m,1H), 7.30-7.32(m, 4H); LRMS APCI m/z 278 [M+H]⁺

PREPARATION 6 Tert-Butyl (3R)-3-(Benzyloxy)Pyrrolidine-1-Carboxylate

The title compound was prepared from (R)-(−)-N-boc-3-pyrrolidinol andbenzyl bromide, using the same method as that described for preparation5. The crude compound was purified by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, toafford the desired product in 97% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.46(s, 3H), 1.92-2.02(m, 1H), 2.03-2.10(m,1H), 3.35-3.48(m, 4H), 4.14-4.19(m, 1H), 4.49-4.57(m, 2H), 7.24-7.33(m,5H)

PREPARATION 7 (3S)-3-Phenoxypyrrolidine Hydrochloride

A mixture of the product of preparation 3 (5.25 g, 19.96 mmol) inhydrochloric acid (4N in dioxan, 50 mL) was stirred at room temperaturefor 2 hours. The reaction mixture was then concentrated in vacuo toafford the title compound as a white solid in 100% yield.

¹HNMR(400 MHz, CD₃OD) δ: 2.29-2.33(m, 2H), 3.42-3.56(m, 4H),5.18-5.21(m, 1H), 6.95-7.01(m, 3H), 7.29-7.32(m, 2H); LRMS APCI m/z 164[M+H]⁺

PREPARATION 8 (3S)-3-(3-Methoxyphenoxy)Pyrrolidine

A mixture of the product of preparation 4 (3.19 g, 10.8 mmol) inhydrochloric acid (4N in dioxan, 27 mL) was stirred at room temperaturefor 3 hours. The reaction mixture was then concentrated in vacuo and theresidue was purified by column chromatography using an Isolute® SCX-2cartridge, eluting with methanol followed by 1M ammonia in methanol, toafford the title compound as a yellow oil in 85% yield, 1.77 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.91-1.98(m, 1H), 2.02-2.11(m, 1H),2.85-2.91(m, 1H), 3.02-3.08(m, 3H), 3.75(s, 3H), 4.85-4.89(m, 1H),6.43-6.51(m, 3H), 7.12-7.16(m, 1H); LRMS APCI m/z 194 [M+H]⁺

PREPARATION 9 (3S)-3-(Benzyloxy)Pyrrolidine Hydrochloride

The title compound was prepared from the product of preparation 5, usingthe same method as that described for preparation 7, as a solid in 100%yield.

¹HNMR(400 MHz, CD₃OD) δ: 2.02-2.12(m, 1H), 2.22-2.29(m, 1H),3.26-3.46(m, 4H), 4.35-4.37(m, 1H), 4.55(s, 2H), 7.25-7.37(m, 5H); LRMSAPCI m/z 178 [M+H]⁺

PREPARATION 10 (3R)-3-(Benzyloxy)Pyrrolidine Hydrochloride

The title compound was prepared from the product of preparation 6, usingthe same method as that described for preparation 7, as a solid in 100%yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.96-2.05(m, 1H), 2.20-2.15(m, 1H),3.49-3.32(m, 4H), 4.23-4.25(m, 1H), 4.44-4.54(m, 2H), 7.26-7.36(m, 5H),9.74-9.88(m, 2H); LRMS APCI m/z 178 [M+H]⁺

PREPARATION 115-Oxo-5-[(3S)-3-Phenoxypyrrolidin-1-yl]-2,2-Diphenylpentanenitrile

A mixture of the products of preparations 2 (2.40 g, 9.05 mmol) and 7(1.99 g, 9.96 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.55 g, 9.96 mmol), 1-hydroxybenzotriazole hydrate (1.35g, 9.96 mmol) and triethylamine (1.38 mL, 9.96 mmol) in dichloromethane(40 mL) was stirred at room temperature for 18 hours. The reactionmixture was then diluted with dichloromethane (100 mL), washed with 1Mhydrochloric acid (70 mL), 1M sodium hydroxide solution (30 mL) andbrine (30 mL), dried over sodium sulfate and concentrated in vacuo. Theresidue was re-crystallised from hot ethanol to afford the titlecompound as a crystalline solid in 76% yield, 2.83 g.

¹HNMR(400 MHz, CD₃OD) δ: 2.07-2.21(m, 2H), 2.33-2.38(m, 1H),2.43-2.47(m, 1H), 2.69-2.84(m, 2H), 3.44-3.55(m, 2H), 3.58-3.67(m, 2H),4.96-5.04(m, 1H), 6.89(d, 2H), 6.93-6.96(m, 1H), 7.24-7.46(m, 12H); LRMSAPCI m/z 412 [M+H]⁺

PREPARATION 125-Oxo-5-[(3R)-3-Phenoxypyrrolidin-1-yl]-2,2-Diphenylpentanenitrile

The title compound was prepared from (3R)-3-phenoxypyrrolidine (WO2005/061457) and the product of preparation 2, using the same method asthat described for preparation 11, to afford the title compound in 41%yield.

PREPARATION 135-[(3S)-3-(3-Methoxyphenoxy)Pyrrolidin-1-yl]-5-Oxo-2,2-Diphenylpentanenitrile

The title compound was prepared from the products of preparations 2 and8, using the same method as that described for preparation 11. The crudecompound was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 98:2:0.2 to 95:5:0.5, toafford the desired product as a colourless oil in quantitative yield.

¹HNMR(400 MHz, CD₃OD) δ: 2.03-2.20(m, 2H), 2.32-2.37(m, 1H),2.43-2.47(m, 1H), 2.66-2.84(m, 2H), 3.44-3.67(m, 4H), 3.74(s, 3H),4.94-5.00(m, 1H), 6.44-6.55(m, 3H), 7.13-7.19(m, 1H), 7.28-7.46(m, 10H);LRMS APCI m/z 412 [M+H]⁺

PREPARATION 145-[(3S)-3-(Benzyloxy)Pyrrolidin-1-yl]-5-Oxo-2,2-Diphenylpentanenitrile

The title compound was prepared from the products of preparation 2 and9, using the same method as that described for preparation 11, as a paleorange solid in 70% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.86-2.15(m, 2H), 2.32-2.43(m, 2H),2.75-2.82(m, 2H), 3.35-3.62(m, 4H), 4.14-4.21(m, 1H), 4.45-4.56(m, 2H),7.22-7.44(m, 15H); LRMS APCI m/z 412 [M+H]⁺

PREPARATION 155-[(3R)-3-(Benzyloxy)Pyrrolidin-1-yl]-5-Oxo-2,2-Diphenylpentanenitrile

N,N′-Carbonyldiimidazole (27 g, 162 mmol) was added to a solution of theproduct of preparation 2 (36 g, 135 mmol) in tetrahydrofuran (600 mL)and the mixture was stirred for 3 hours at room temperature. A solutionof the product of preparation 10 (31 g, 141.75 mmol) in tetrahydrofuran(300 mL) was added and the mixture was stirred at room temperature for18 hours. The reaction mixture was then filtered, washing through withtetrahydrofuran, and the filtrate was concentrated in vacuo. The residuewas partitioned between water (200 mL) and ethyl acetate (600 mL) andthe organic layer was separated, washed with water, 2N hydrochloric acid(2×100 mL) and brine, dried over magnesium sulfate and concentrated invacuo. Trituration of the residue with diethyl ether then afforded thetitle compound in 83% yield, 48.2 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.87-2.15(m, 2H), 2.32-2.44(m, 2H),2.74-2.82(m, 2H), 3.35-3.61(m, 4H), 4.14-4.22(m, 1H), 4.46-4.57(m, 2H),7.23-7.44(m, 15H); LRMS APCI m/z 425 [M+H]⁺

PREPARATION 165-[(3S)-3-Hydroxpyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanamide

Iron (III) chloride (1.57 g, 9.70 mmol) was added to a solution of theproduct of example 11 (385 mg, 0.84 mmol) in dichloromethane (10 mL) andthe mixture was stirred at room temperature for 3 hours. The reactionwas quenched by the addition of 2M hydrochloric acid (6 mL), filteredthrough Arbocel® and the filtrate was basified with 0.88 ammoniasolution (20 mL). The layers of the filtrate were separated and theaqueous solution was extracted with dichloromethane (2×25 mL). Thecombined organic solution was dried over sodium sulfate, concentrated invacuo and purification of the residue by column chromatography on silicagel, eluting with ethyl acetate:methanol:0.88 ammonia, 95:5:0.5 to85:15:1.5, afforded the title compound as a brown gum in 60% yield, 415mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 6H), 1.23-1.27(m, 2H), 1.56-1.64(m,1H), 1.89-1.98(m, 1H), 2.40-2.44(m, 3H), 2.47-2.52(m, 1H), 2.61-2.67(m,1H), 2.74-2.78(m, 1H), 4.17-4.22(m, 1H), 7.22-7.26(m, 2H), 7.29-7.33(m,4H), 7.37(d, 4H); LRMS APCI m/z 367 [M+H]⁺

PREPARATION 175-[(3R)-3-Hydroxypyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanamide

1N Hydrochloric acid (10.95 mL, 10.95 mmol) and 20% Pd(OH)₂ (19) wereadded to a solution of the product of example 9 (5 g, 10.95 mmol) inethanol (250 mL) and the mixture was stirred at 50° C., under 50 psi ofhydrogen gas, for 4 hours. The reaction mixture was then filteredthrough Arbocel® and the filtrate was concentrated in vacuo to give awhite foam. The foam was re-dissolved in ethanol (250 mL), 20% Pd(OH)₂(19) was added and the mixture was stirred at 50° C., under 50 psi ofhydrogen gas, for 24 hours. The reaction mixture was then filteredthrough Arbocel®, washing through with ethanol, and the filtrate wasconcentrated in vacuo. The residue was suspended in 0.88 ammonia,extracted with ethyl acetate (3×50 mL) and the combined organic solutionwas washed with brine (50 mL), dried over sodium sulfate andconcentrated in vacuo to afford the title compound as a white foam in90% yield, 3.63 g.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 6H), 1.23-1.27(m, 2H), 1.56-1.63(m,1H), 1.89-1.96(m, 1H), 2.39-2.44(m, 3H), 2.46-2.52(m, 1H), 2.61-2.67(m,1H), 2.74-2.78(m, 1H), 4.17-4.22(m, 1H), 7.22-7.26(m, 2H), 7.29-7.33(m,4H), 7.36-7.39(m, 4H); LRMS APCI m/z 367 [M+H]⁺

PREPARATION 185-[(3S)-3-Hydroxypyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanenitrile

Iron (III) chloride (1.33 g, 8.22 mmol) was added to a solution of theproduct of example 10 (1.2 g, 2.74 mmol) in dichloromethane (25 mL) andthe mixture was stirred at room temperature for 3 hours. The solvent wasremoved in vacuo and the residue was partitioned between 2M hydrochloricacid (aq) (20 mL) and diethyl ether (30 mL). The aqueous layer wasseparated and basified to pH14 with solid sodium hydroxide. Theresulting brown precipitate was collected by filtration and purified bycolumn chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 85:15:1.5, to affordthe title compound as a colourless gum in 50% yield, 475 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.11(s, 6H), 1.52-1.56(m, 2H), 1.69-1.76(m,1H), 1.95-2.04(m, 1H), 2.53-2.57(m, 2H), 2.62-2.65(m, 1H), 2.69-2.76(m,1H), 2.83-2.95(m, 2H), 4.27-4.31(m, 1H), 7.29-7.33(m, 2H), 7.36-7.45(m,8H); LRMS APCI m/z 349 [M+H]⁺

PREPARATION 195-{(3S)-3-[(6-{[Tert-Butyl(Dimethyl)silyl]Oxy}-2-Naphthyl)Oxy]Pyrrolidin-1-Yl}-5-Methyl-2,2-Diphenylhexanamide

1,1′-Azobis(N,N′-dimethylformamide) (95 mg, 0.553 mmol) was added to anice-cooled solution of triphenyl phosphine (145 mg, 0.553 mmol),6-(tert-Butyldimethylsilyloxy)-2-naphthol [(102 mg, 0.372 mmol)EP625510, p 13] and the product from preparation 17 (150 mg, 0.41 mmol)in tetrahydrofuran (5 mL) and the mixture was heated at 60° C. for 18hrs. Additional triphenyl phosphine (145 mg, 0.553 mmol) and1,1′-Azobis(N,N′-dimethylformamide) (95 mg, 0.553 mmol) were added andheating continued for a further 18 hrs. The mixture was concentrated invacuo and the residue purified using an Isolute® SCX-2 cartridge,eluting with methanol, then with 0.25M ammonia in methanol. Basicfractions were concentrated in vacuo and further purified using aRediSep® silica gel cartridge, eluting withdichloromethane:methanol:0.88 ammonia (100:0:0 to 92:8:0.8) to affordthe title compound in 20% yield, 46 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.24(s, 6H), 0.95(s, 3H), 1.04(s, 9H), 1.06(s,3H) 1.15-1.29(m, 2H), 1.88-1.99(m, 1H), 2.11-2.22(m, 1H), 2.30-2.52(m,2H), 2.54-2.62(m, 1H), 2.64-2.69(m, 1H), 2.72-2.82(m, 1H), 2.82-2.90(m,1H), 4.83-4.89(m, 1H), 6.96-7.06(m, 2H), 7.12-7.34(m, 12H), 7.53-7.57(m,1H), 7.60-7.65(m, 1H); LRMS APCI m/z 623 [M+H]⁺

PREPARATION 205-[(3R)-3-Hydroxypyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanenitrile

Iron (III) chloride (13.3 g, 82.192 mmol) was added to a solution of theproduct of example 8 (9 g, 20.548 mmol) in dichloromethane (200 mL) andthe mixture was stirred at room temperature for 1 hour. The reaction wasquenched by addition of 2M hydrochloric acid (150 mL) and stirred for 30minutes. The organic layer was separated and the aqueous re-extractedwith a further 100 ml dichloromethane. The combined organic layers weredried over sodium sulphate and concentrated in vacuo. Purification bycolumn chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 90:1:1.0, affordedthe title compound as a pale brown foam in 89% yield, 6.37 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.18(s, 6H), 1.58-1.62(m, 2H), 1.76-1.84(m,1H), 1.96-2.05(m, 1H), 2.55-2.59(m, 2H), 2.74-2.81(m, 1H), 2.87-2.93(m,1H), 2.98-3.06(m, 2H), 4.32-4.36(m, 1H), 7.30-7.34(m, 2H), 7.37-7.46(m,8H); LRMS APCI m/z 349 [M+H]⁺

PREPARATION 21 2-Chloro-3-Methoxyphenol

3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise toa solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) indichloromethane (12 ml) and the mixture was stirred for 3 hours at roomtemperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) wasadded and mixture allowed to stir for 18 hrs. The solution was dilutedwith 12 ml dichloromethane and washed with saturated sodium sulphitesolution (15 ml) and saturated sodium hydrogen carbonate solution (15ml). The organic layer was dried over sodium sulphate and concentratedin vacuo to a yellow gum. The residue was dissolved in methanol (12 ml),triethylamine (0.05 ml) was added and the mixture stirred for 18 hoursat room temperature. The solution was concentrated in vacuo, dissolvedin diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml).The aqueous layer was acidified to pH1 by dropwise addition of 2Nhydrochloric acid and extracted with diethyl ether (2×25 ml). Thesecombined organic layers were dried over sodium sulphate and concentratedin vacuo to afford the title compound as a brown gum in 70% yield, 325mg.

¹HNMR(400 MHz, CD₃OD) δ: 3.83(s, 3H), 6.52-6.54(d, 2H), 7.01-7.06(t, 1H)

PREPARATION 22 1-Chloro-3-Fluoro-2-Methoxybenzene

Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg,6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) intetrahydrofuran (10 ml) and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was partitioned between diethyl ether(50 ml) and water (50 ml). The organic phase was extracted and furtherwashed with water (2×20 ml) then dried over sodium sulphate andconcentrated in vacuo to afford the title compound as a colourlessliquid in 94% yield, 1.03 g.

¹HNMR(400 MHz, CD₃OD) δ: 3.90-3.91 (s, 3H), 7.01-7.12(m, 2H),7.18-7.21(m, 1H)

PREPARATION 23 3-Fluoro-5-Methoxyphenol

Boron tribromide (1M in dichloromethane, 9 mL, 89.985 mmol) was addeddrop wise to an ice-cooled solution of 3,5-dimethoxy fluorobenzene (3ml, 22.496 mmol) in dichloromethane (20 mL) and the mixture was stirredat 0° C. to room temperature for 4 hours. The solution was cooled to 0°C., further boron tribromide (4 ml, 44.992 mmol) was added and stirringcontinued, warming to room temperature for an additional 18 hours. Thereaction was quenched with 0.88 ammonia solution and stirred at roomtemperature for 90 minutes. The organic layer was separated andextracted with 2N sodium hydroxide (30 ml), which was then acidified topH1 by drop wise addition of concentrated hydrochloric acid. The aqueouslayer was then re-extracted with dichloromethane (3×15 mL), the combinedorganic solution was dried over sodium sulfate and concentrated in vacuoto afford the title compound as a white solid in 54% yield, 1.72 g.

¹HNMR(400 MHz, CD₃OD) δ: 3.72(s, 3H), 6.07-6.15(m, 3H)

PREPARATION 24 1-Fluoro-3-Methoxy-5-Trifluoromethyl-benzene

The title compound was prepared from 3-fluoro-5-trifluoromethylphenol,using the same method as that described for preparation 22 to afford acolourless oil in 90% yield.

¹HNMR(400 MHz, CD₃OD) δ: 3.84(s, 3H), 6.92-6.97(m, 2H), 7.00(s, 1H)

PREPARATION 25 4-Fluoro-3-Methoxyphenol

The title compound was prepared from 4-fluoro-3-methoxybenzaldehyde,using the same method as that described for preparation 21, to afford abrown oil in 55% yield.

¹HNMR(400 MHz, CD₃OD) δ: 3.79(s, 3H), 6.23-6.27(m, 1H), 6.47-6.50(dd,1H), 6.81-6.86(m, 1H)

PREPARATION 26 2-Fluoro-3-Methoxyphenol

The title compound was prepared from 2-fluoro-3-methoxybenzaldehyde,using the same method as that described for preparation 21, to afford abrown oil in 33% yield.

¹HNMR(400 MHz, CD₃OD) δ: 3.82(s, 3H), 6.47-6.55(m, 2H), 6.82-6.87(t, 1H)

PREPARATION 27 1-Allyloxy-3-Bromomethyl-benzene

To a solution of (3-allyloxy-phenyl)-methanol (Tetrahedron, 2000,56(13), 1873-1882) (1.07 g, 6.49 mmol) in THF (7 mls) at 3° C. was addedcarbon tetrabromide (2.69 g, 8.11 mmol) then triphenylphosphine (2.13 g,8.11 mmol) in THF (2 mls). The reaction mixture was stirred at 5° C. for1 hour. The reaction mixture was filtered and concentrated in vacuo. Theresidue was washed with pentane to give a yellow solid which waspurified by column chromatography on silica gel, eluting withpentane:ethyl acetate, 100:0, to 95:5 to afford the title compound as apale yellow oil in 24% yield, 350 mg.

¹HNMR(400 MHz, CDCl₃) δ: 4.47 (s, 2H), 4.51-4.60 (m, 2H), 5.26-5.35 (m,1H), 5.37-5.47 (m, 1H), 5.99-6.11 (m, 1H), 6.82-6.90 (m, 1H), 6.92-7.01(m, 2H), 7.21-7.30 (m, 1H).

PREPARATION 285-[(3R)-3-(3-Allyloxy-benzyloxy)-pyrrolidin-1-yl]-5-Methyl-2,2-Diphenyl-hexanenitrile

The product of preparation 20 (179 mg, 0.514 mmol) in dimethylformamide(3 ml) was added drop wise to an ice-cooled solution of sodium hydride(60% dispersion in mineral oil, 31 mg, 0.770 mmol) in dimethylformamide(1 ml). After stirring for 1 hour the product of preparation 27 (175 mg,0.514 mmol) in dimethylformamide (1 ml) was added and the mixture wasallowed to warm to room temperature for 18 hours. The reaction mixturewas then re-cooled to 0° C. and further sodium hydride (60% dispersionin mineral oil, 31 mg, 0.770 mmol) added, with stirring at roomtemperature for an additional 3 hours. The solution was quenched bydropwise addition of water, concentrated in vacuo and partitionedbetween ethyl acetate (10 ml) and water (10 ml). The organic layer wasextracted and washed with water (10 ml), then dried over sodium sulphateand concentrated in vacuo. Purification by column chromatography onsilica gel, eluting with dichloromethane:methanol:0.88 ammonia,97:3:0.3, afforded the title compound as a pale yellow gum in 43% yield,108 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.05(s, 3H), 1.44-1.51(m, 2H),1.78-1.85(m, 1H), 1.93-2.01(m, 1H), 2.50-2.55(m, 3H), 2.64-2.78(m, 3H),4.03-4.08(m, 1H), 4.43(s, 2H), 4.50-4.55(m, 2H), 5.20-5.24(m, 1H),5.34-5.41(m, 1H), 5.98-6.09(m, 1H), 6.79-6.84(m, 1H), 6.87-6.94(m, 2H),7.18-7.21(t, 1H), 7.26-7.43(m, 10H); LRMS ESI m/z 495 [M+H]⁺

PREPARATION 295-Methyl-2,2-Diphenyl-5-[(3R)-3-(3-Propenyloxy-benzyloxy)-pyrrolidin-1-yl]-Hexanoicacidamide

The title compound was prepared from the product of preparation 28,using the same method as that described for example 2, with the additionof further potassium hydroxide (2 eq) after 20 hours and continuedheating for an additional 4 hrs to afford product as a yellow gum in 88%yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.01(s, 3H), 1.23-1.28(m, 2H),1.67-1.69(d, 3H), 1.74-1.82(m, 1H), 1.88-1.95(m, 1H), 2.40-2.44(m, 2H),2.47-2.53(m, 1H), 2.55-2.74(m, 3H), 3.99-4.04(m, 1H), 4.42(s, 2H),4.85-4.87(m, 1H), 6.40-6.42(d, 1H), 6.88-6.90(d, 1H), 6.96-6.99(m, 2H),7.21-7.38(m, 11H); LRMS ESI m/z 513 [M+H]⁺

PREPARATION 30 3-Allyloxy-4-Fluoro-Benzoic Acid Ally Ester

Allyl bromide (3.04 ml, 35.2 mmol) was added dropwise to a suspension of4-fluoro-3-hydroxybenzoic acid (2.5 g, 16.0 mmol) and potassiumcarbonate (4.43 g, 32.03 mmol) in dimethylformamide (50 ml) at roomtemperature and the mixture was stirred for 18 hrs. The solvent wasremoved in vacuo and the residue partitioned between diethyl ether (30ml) and water (30 ml). The aqueous layer was separated and extractedwith further diethyl ether (2×20 ml). The combined organic layers werewashed with water (3×10 ml), dried over sodium sulfate and concentratedin vacuo to afford the title compound as a colourless liquid in 100%yield, 3.82 g.

¹HNMR(400 MHz, CDCl₃) δ: 4.65-4.66(d, 2H), 4.80-4.82(d, 2H),5.28-5.48(m, 4H), 5.98-6.12(m, 2H), 7.10-7.14(dd, 1H), 7.65-7.69(m, 2H);LRMS APCI m/z 237 [M+H]⁺

PREPARATION 31 (3-Allyloxy-4-Fluoro-phenyl)-Methanol

A solution of the product of preparation 30 (2.0 g, 8.47 mmol) intetrahydrofuran (30 ml) was added dropwise over 20 minutes to a solutionof lithium aluminium hydride in tetrahydrofuran (1M, 16.9 ml, 16.9 mmol)at 0° C. under a nitrogen atmosphere, and the solution allowed to warmto room temperature over 5 hrs. The mixture was cooled to 0° C. andquenched by sequential dropwise addition of water (1 ml), aqueous sodiumhydroxide solution (2M, 2 ml) and water (3 ml), and the mixture stirredat room temperature for 18 hrs. The mixture was filtered through Celite®and the filter pad washed with ethyl acetate (3×20 ml). The filtrate wasseparated and the organic layer washed with brine (10 ml), dried oversodium sulfate and concentrated in vacuo to afford the title compound asa colourless liquid in 100% yield, 1.75 g.

¹HNMR(400 MHz, CDCl₃) δ: 4.61-4.63(m, 4H), 5.29-5.32(d, 1H),5.41-5.45(d, 1H), 6.02-6.11(m, 1H), 6.85-6.89(m, 1H), 7.00-7.07(m, 2H);LRMS APCI m/z 165 [M−OH]⁺

PREPARATION 32 2-Allyloxy-4-Bromomethyl-1-Fluorobenzene

Dibromotriphenylphosphorane (2.3 g, 5.43 mmol) was added to a solutionof the product from preparation 31 (900 mg, 4.94 mmol) in acetonitrile(40 ml) at room temperature and the solution stirred for 18 hrs. Thesolvent was removed in vacuo and the residue purified by columnchromatography on silica gel, eluting with pentane:ethyl acetate (80:20)to afford the title compound as a colourless liquid in 31% yield, 380mg.

¹HNMR(400 MHz, CDCl₃) δ: 4.44(s, 2H), 4.61-4.63(m, 2H), 5.30-5.34(m,1H), 5.41-5.47(m, 1H), 6.02-6.11(m, 1H), 6.91-6.94(m, 1H), 6.99-7.05(m,2H); LRMS APCI m/z 165 [M−Br]⁺

PREPARATION 335-[(3R)-3-(3-Allyloxy-4-Fluoro-benzyloxy)-Pyrrolidin-1-Yl]-5-Methyl-2,2-Diphenylhexanenitrile

Sodium hydride (62 mg, 1.55 mmol) was added portionwise to an ice-cooledsolution of the product of preparation 20 (270 mg, 0.775 mmol) indimethylformamide (3 ml) under a nitrogen atmosphere. After stirring for1.5 hrs a solution of the product of preparation 32 (380 mg, 1.55 mmol)in dimethylformamide (2 ml) was added and the mixture was allowed towarm to room temperature and stirred for 18 hours. The solvent wasremoved in vacuo and the residue partitioned between ethyl acetate (10ml) and saturated sodium hydrogen carbonate solution (5 ml). The aqueouslayer was separated and extracted with further ethyl acetate (10 ml).The combined organic layers were washed with water (5 ml), brine (5 ml),dried over sodium sulphate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia (99:1:0.1 to 98:2:0.2 to 95:5:0.5)to afford the title compound as a yellow oil in 38% yield, 150 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.06(s, 3H), 1.44-1.53(m, 2H),1.78-1.86(m, 1H), 1.93-2.02(m, 1H), 2.50-2.57(m, 3H), 2.67-2.79(m, 3H),4.03-4.07(m, 1H), 4.41(s, 2H), 4.56-4.58(m, 2H), 5.22-5.26(m, 1H),5.36-5.41(m, 1H), 5.99-6.08(m, 1H), 6.85-6.88(m, 1H), 6.98-7.06(m, 2H),7.28-7.43(m, 10H); LRMS ESI m/z 513 [M+H]⁺

PREPARATION 345-[(3R)-3-(4-Fluoro-3-Propenyloxy-benzyloxy)-Pyrrolidin-1-Yl]-5-Methyl-2,2-Diphenylhexanamide

The title compound was prepared from the product of preparation 33,using the same method as that described for example 2 to afford acolourless oil in 100% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.04(s, 3H), 1.23-1.32(m, 2H),1.69-1.71(d, 3H); 1.77-1.86(m, 1H), 1.89-1.97(m, 1H), 2.40-2.82(m, 6H),4.02-4.07(m, 1H), 4.39(s, 2H), 4.88-4.95(m, 1H), 6.37-6.40(m, 1H),6.95-6.99(m, 1H), 7.04-7.11 (m, 2H), 7.22-7.38(m, 10H); LRMS ESI m/z 531[M+H]⁺

PREPARATION 35 3-Benzyloxy-5-Hydroxy-benzonitrile

Caesium carbonate (2.41 g, 7.4 mmol) was added to a solution of3,5-dihydroxy benzonitrile (1.0 g, 7.4 mmol) in dimethylformamide (5 ml)at room temperature and the mixture stirred for 10 minutes. Benzylbromide (0.880 ml, 7.4 mmol) was added dropwise and the mixture heatedat 80° C. for 30 minutes. The solvent was removed in vacuo, the residuetreated with water (10 ml), acidified with aqueous hydrochloric acid(2M) and extracted with ethyl acetate (3×25 ml). The combined organiclayers were washed with water (2×10 ml), brine (10 ml), dried oversodium sulphate and concentrated in vacuo. The residue was purified bycolumn chromatography, eluting with ethyl acetate/pentane (20:80 to50:50) to afford the title compound as a white solid in 26% yield, 445mg.

¹HNMR(400 MHz, CD₃OD) δ: 5.07(s, 2H), 6.67-6.70(m, 2H), 6.80(d, 1H),7.29-7.43(m, 5H); LRMS ESI m/z 224 [M]⁻

PREPARATION 365-[(3S)-3-(3-Benzyloxy-5-Cyano-phenoxy)-Pyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanamide

Diisopropyl azodicarboxylate (215 μL, 1.09 mmol) was added dropwise toan ice-cooled solution of triphenyl phosphine (286 mg, 1.09 mmol), theproduct from preparation 35 (369 mg, 1.64 mmol) and the product frompreparation 17 (200 mg, 0.546 mmol) in tetrahydrofuran (10 mL), and themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated in vacuo and purified using an Isolute® SCX-2 cartridge,eluting with methanol, then with 1M ammonia in methanol. Basic fractionswere concentrated in vacuo and further purified by column chromatographyon silica gel, eluting with dichloromethane:methanol:0.88ammonia(98:2:0.2 to 97:3:0.3) to afford the title compound as an orange foam in25% yield, 80 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.02(s, 3H), 1.20-1.28(m, 3H),1.81-1.87(m, 1H), 2.07-2.16(m, 1H), 2.34-2.83(m, 5H), 4.74-4.79(m, 1H),5.10(s, 2H), 6.72-6.74(m, 2H), 6.93(s, 1H), 7.20-7.43(m, 15H); LRMS ESIm/z 574 [M+H]⁺

PREPARATION 375-{(3S)-3-[(7-{[tert-Butyl(Dimethyl)Silyl]Oxy}-2-Naphthyl)Oxy]Pyrrolidin-1-yl}-5-Methyl-2,2-Diphenylhexanamide

A solution of 1,1′-Azobis(N,N′-dimethylformamide) (109 mg, 0.630 mmol)in tetrahydrofuran (2 ml) was added dropwise to an ice-cooled solutionof triphenyl phosphine (165 mg, 0.630 mmol),7-[[dimethyl(1,1-dimethylethyl)silyl]oxy]naphthalen-2-ol [(115 mg, 0.420mmol), Journal of Medicinal Chemistry, 1993, Vol. 36, No. 22, p 3316]and the product from preparation 17 (171 mg, 0.467 mmol) intetrahydrofuran (3 mL), and the mixture was stirred at room temperaturefor 72 hours, then 60° C. for 18 hrs. The mixture was concentrated invacuo and the residue purified using an Isolute® SCX-2 cartridge,eluting with methanol, then with 0.5M ammonia in methanol. Basicfractions were concentrated in vacuo and further purified using aRediSep® silica gel cartridge, eluting withdichloromethane:methanol:0.88 ammonia (100:0:0 to 92:8:0.8) to affordthe title compound as a colourless gum in 34% yield, 90 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.25(s, 6H), 0.95-1.10(m, 15H), 1.19-1.33(m,2H), 1.95(m, 1H), 2.18(m, 1H), 2.34-2.52(m, 2H), 2.56-2.75(m, 2H),2.76-2.86(m, 1H), 2.87-2.94(m, 1H), 4.90(m, 1H), 6.83-6.96(m, 3H),7.12(m, 1H), 7.13-7.36(m, 10H), 7.58-7.66(m, 2H); LRMS APCI m/z 623[M+H]⁺

PREPARATION 38 3-Methoxy-4-Chloro-Benzoic Acid Allyl Ester

Potassium carbonate (4.44 g, 32.156 mmol) and allyl bromide (2.78 ml,32.156 mmol) were added to a stirred solution of4-chloro-3-methoxybenzoic acid (3 g, 16.078 mmol) inN,N-dimethylformamide (30 ml) and allowed to stir at room temperaturefor 18 hours. The reaction mixture was partitioned between diethyl ether(200 ml) and water (150 ml), the organic phase extracted and furtherwashed with water (150 ml), dried over sodium sulfate and concentratedin vacuo to afford the title compound as an orange oil in 98% yield,3.57 g.

¹HNMR(400 MHz, CD₃OD) δ: 3.92(s, 3H), 4.79-4.82(d,2H), 5.26-5.29(d,1H),5.37-5.42(d, 1H), 6.00-6.10(m, 1H), 7.44-7.46(d, 1H), 7.56-7.59(dd, 1H),7.62-7.63(d, 1H); LRMS ESI m/z 227 [M+H]⁺

PREPARATION 39 3-Hydroxy-4-Chloro-Benzoic-Acid

Boron tribromide (1M in dichloromethane, 31 mL, 31.504 mmol) was addedto an ice-cooled solution of the product of preparation 38 (3.56 g,15.752 mmol) in dichloromethane (30 mL) and the mixture was stirred at0° C. to room temperature for 18 hours. The reaction was quenched with0.88 ammonia solution and stirred at room temperature for 90 minutes.The reaction mixture was acidified to pH 1 by dropwise addition of 2Nhydrochloric acid (aq) and extracted with diethyl ether (2×50 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to afford the title compound as a pale yellow solid in 90%yield, 2.45 g.

¹HNMR(400 MHz, CD₃OD) δ: 7.36-7.38(d, 1H), 7.44-7.47(dd, 1H),7.54-7.55(d, 1H); LRMS APCI m/z 171 [M−H]⁻

PREPARATION 40 3-Allyloxy-4-Chloro-Benzoic Acid Allyl Ester

Potassium carbonate (4.9 g, 35.057 mmol) and allyl bromide (3.07 ml,35.507 mmol) were added to a stirred solution of the product ofpreparation 39 (2.45 g, 14.203 mmol) in N,N-dimethylformamide (30 ml)and allowed to stir at room temperature for 18 hours. The reactionmixture was partitioned between diethyl ether (70 ml) and water (70 ml),the organic phase was then extracted and further washed with water (50ml), dried over sodium sulfate and concentrated in vacuo. The residuewas purified by column chromatography on silica gel, eluting withpentane:ethyl acetate, 100:0 to 90:10, to afford the title compound as apale orange oil in 74% yield, 2.65 g.

¹HNMR(400 MHz, CD₃OD) δ: 4.66-4.68(d, 2H), 4.79-4.81(d, 2H),5.25-5.31(t,2H), 5.36-5.49(q, 2H), 6.00-6.12(m, 2H), 7.45-7.47(d, 1H),7.56-7.59(dd, 1H), 7.62(d, 1H)

PREPARATION 41 (3-Allyloxy-4-Chloro-Phenyl)-Methanol

A solution of the product of preparation 40 (2.6 g, 10.30 mmol) intetrahydrofuran (40 ml) was added dropwise to a stirred solution oflithium aluminium hydride (1M in tetrahydrofuran, 21 ml, 20.60 mmol)over 30 minutes at room temperature and allowed to stir for 18 hours.The reaction mixture was quenched by dropwise addition of water (1 ml),2M sodium hydroxide (2 ml) and water (3 ml) and allowed to stir for 3hours. The mixture was then filtered, washing with diethyl ether (2×20ml) and water (10 ml). The organic phase was extracted, dried oversodium sulfate and concentrated in vacuo to afford the title compound asa colourless oil in 69% yield, 1.4 g.

¹HNMR(400 MHz, CD₃OD) δ: 4.50(s, 2H), 4.60-4.62(d, 2H), 5.24-5.28(d,1H), 5.42-5.48(d, 1H), 6.03-6.12(m, 1H), 6.87-6.90(d, 1H), 7.05(s, 1H),7.29-7.31(d, 1H); LRMS ESI m/z 198 [M+H]⁺

PREPARATION 42 2-Allyloxy-4-Bromomethyl-1-Chlorobenzene

Dibromotriphenylphosphorane (3.27 g, 7.758 mmol) was added to a stirredsolution of the product of preparation 41 (1.4 g, 7.053 mmol) inacetonitrile (50 ml) and allowed to stir at room temperature for 18hours. Further dibromotriphenylphosphorane (3.27 g, 7.758 mmol) wasadded and the reaction mixture stirred at room temperature for a further6 hours. The solution was then concentrated in vacuo and recrystallisedfrom hot ethyl acetate (25 ml) and diethyl ether (25 ml). The solid wasfiltered from solution and the filtrate concentrated in vacuo. Theresidue was purified by column chromatography on silica gel, elutingwith pentane:ethyl acetate, 100:0 to 80:20, to afford the title compoundas a colourless oil in 48% yield, 890 mg.

¹HNMR(400 MHz, CD₃OD) δ: 4.52(s, 2H), 4.61-4.63(d, 2H), 5.25-5.29(d,1H), 5.42-5.48(d, 1H), 6.02-6.11 (m, 1H), 6.95-6.98(d, 1H), 7.10(d, 1H),7.30-7.32(d, 1H)

PREPARATION 435-[(3R)-3-(3-Allyloxy-4-Chloro-Benzyloxy)-Pyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanenitrile

A solution of the product of preparation 20 (180 mg, 0.515 mmol) inN,N-dimethylformamide (3 ml) was added to an ice-cooled solution ofsodium hydride (60% dispersion in mineral oil, 41 mg, 1.032 mmol) inN,N-dimethylformamide (2 mL) and the mixture was stirred at 0° C. for 30minutes. The product of preparation 42 (270 mg, 1.032 mmol) was addedand the mixture was stirred for 18 hours at 0° C. to room temperature.The reaction was ice-cooled, further sodium hydride (41 mg, 1.032 mmol)was added and the mixture was stirred for a further 3 hours at roomtemperature. The reaction mixture was then quenched with water (3 mL),concentrated in vacuo and the aqueous residue was partitioned betweenethyl acetate (30 mL) and water (20 mL). The organic layer was separatedand washed with water (2×20 mL), then concentrated in vacuo. The residuewas purified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5, to afford the titlecompound as a brown gum in 62% yield, 170 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.05(s, 3H), 1.43-1.52(m, 2H),1.78-1.86(m, 1H), 1.93-2.02(m, 1H), 2.49-2.56(m, 3H), 2.65-2.79(m, 3H),4.03-4.08(m, 1H), 4.43(s, 2H), 4.56-4.58(d, 2H), 5.22-5.26(d, 1H),5.39-5.45(d, 1H), 5.99-6.08(m, 1H), 6.85-6.88(dd, 1H), 7.01-7.02(d, 1H),7.26-7.42(m, 11H); LRMS APCI m/z 529 [M+H]⁺

PREPARATION 445-[(3R)-3-(4-Chloro-3-Propenyloxy-Benzyloxy)-Pyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanamide

Potassium hydroxide (340 mg, 6.055 mmol) was added to a solution of theproduct of preparation 43 (160 mg, 0.303 mmol) in 3-methyl-3-pentanol (7mL) and the mixture was heated under reflux for 24 hours. The reactionmixture was then cooled to room temperature, concentrated in vacuo andthe residue was partitioned between ethyl acetate (25 mL) and water (25mL). The aqueous layer was separated, extracted with further ethylacetate (25 mL) and the combined organic layers were dried over sodiumsulfate and concentrated in vacuo to afford the title compound as ayellow gum in 97% yield, 161 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 0.99(s, 3H), 1.21-1.27(m, 2H),1.70-1.72(d, 3H), 1.74-1.80(m, 1H), 1.87-1.93(m, 1H), 2.39-2.44(m, 2H),2.45-2.50(m, 1H), 2.53-2.57(dd, 1H), 2.59-2.65(q, 1H), 2.68-2.72(m, 1H),3.98-4.02(m, 1H), 4.39(s, 2H), 4.93-5.00(m, 1H), 6.38-6.40(m, 1H),6.94-6.97(dd, 1H), 7.04(d, 1H), 7.20-7.39(m, 11H); LRMS APCI m/z 547[M+H]⁺

PREPARATION 455-[(3R)-3-(3-Benzyloxy-4-Cyano-Phenoxy)Pyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanamide

Sodium hydride (60% dispersion in mineral oil, 26 mg, 0.656 mmol) wasadded to an ice-cooled solution of the product of preparation 17 (200mg, 0.546 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred for 60 minutes. 2-Benzyloxy-4-fluoro-benzonitrile (136 mg, 0.601mmol) was added and the mixture was stirred for 18 hours at roomtemperature. The reaction mixture was quenched with water (3 mL),concentrated in vacuo and the aqueous residue was partitioned betweenethyl acetate (20 mL) and water (15 mL). The aqueous layer was separatedand extracted with further ethyl acetate (2×10 mL). The combined organiclayers were concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting withdichloromethane:methanol:0.88ammonia, 95:5:0.5, to afford the titlecompound as a white foam in 33% yield, 105 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.95(s, 3H), 1.02(s, 3H), 1.19-1.25(m, 2H),1.79-1.88(m, 1H), 2.07-2.16(m, 1H), 2.33-2.49(m, 2H), 2.51-2.58(m, 2H),2.67-2.74(m, 1H), 2.79-2.83(m, 1H), 4.80-4.84(m, 1H), 5.20(s, 2H),6.49-6.52(dd, 1H), 6.57-6.58(d, 1H), 7.20-7.38(m, 13H), 7.44-7.46(m,2H), 7.48-7.50(d, 1H); LRMS APCI m/z 574 [M+H]⁺

PREPARATION 46 (3-Allyloxy-2-Chloro-Phenyl)-Methanol

Sodium borohydride (185 mg, 4.883 mmol) was added to a solution of theproduct of preparation 99 (800 mg, 4.07 mmol) in ethanol (30 ml) and themixture stirred at room temperature for 18 hours. The mixture wasquenched by addition of water (30 ml) followed by dropwise addition ofglacial acetic acid until effervescence ceased. The mixture was thenextracted with diethyl ether (2×50 ml) and the combined organic layerswere washed with saturated aqueous sodium hydrogen carbonate solution(40 ml), dried over sodium sulfate and concentrated in vacuo to affordthe title compound as a colourless gum in 100% yield, 805 mg.

¹HNMR(400 MHz, CD₃OD) δ: 4.60-4.62(m, 2H), 4.66-4.69(d, 2H),5.24-5.28(d, 1H), 5.43-5.47(d, 1H), 6.01-6.12(m, 1H), 6.82-6.84(d, 1H),7.09-7.12(m, 1H), 7.22-7.26(m, 1H); LRMS ESI m/z 198 [M+H]⁺

PREPARATION 47 3-Allyloxy-2-Chloro-Benzyl Bromide

Dibromotriphenylphosphorane (1.87 g, 4.431 mmol) was added to a solutionof the product of preparation 46 (800 mg, 4.028 mmol) in acetonitrile(30 ml) and the mixture allowed to stir at room temperature for 18hours. Additional dibromotriphenylphosphorane (1.87 g, 4.431 mmol) wasadded and the mixture stirred at room temperature for a further 6 hours.The solution was concentrated in vacuo and the residue recrystallisedfrom hot ethyl acetate (15 ml) and diethyl ether (15 ml). The solid wasfiltered from solution and the filtrate concentrated in vacuo. Theresidue was purified by column chromatography on silica gel, elutingwith pentane:ethyl acetate, 100:0 to 90:10, to afford the title compoundas a colourless oil in 27% yield, 285 mg.

¹HNMR(400 MHz, CD₃OD) δ: 4.61-4.63(m, 2H), 4.65(s, 2H), 5.26-5.29(d,1H), 5.43-5.49(d, 1H), 6.00-6.11(m, 1H), 7.01-7.03(d, 1H), 7.08-7.10(d,1H), 7.20-7.24(t, 1H); LRMS APCI m/z 262 [M+H]⁺

PREPARATION 485-[(3R)-3-(3-Allyloxy-2-Chloro-Benzyloxy)-Pyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanenitrile

The title compound was prepared from the product of preparation 47 andthe product of preparation 20, using the same method as that describedfor preparation 43, to afford a brown gum in 46% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.05(s, 3H), 1.45-1.51(m, 2H),1.81-1.90(m, 1H), 1.95-2.04(m, 1H), 2.50-2.58(m, 3H), 2.65-2.79(m, 3H),4.07-4.12(m, 1H), 4.49-4.54(m, 2H), 4.59-4.61(m, 2H), 5.24-5.27(d, 1H),5.41-5.47(d, 1H), 6.02-6.11(m, 1H), 6.96-6.98(d, 1H), 7.06-7.08(d, 1H),7.17-7.42(m, 11H); LRMS APCI m/z 529 [M+H]⁺

PREPARATION 495-[(3R)-3-(2-Chloro-3-Propenyloxy-Benzyloxy)-Pyrrolidin-1-yl]-5-Methyl-2,2-Diphenylhexanamide

The title compound was prepared from the product of preparation 48,using the same method as that described for preparation 44, to afford ayellow gum in 100% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.01(s, 3H), 1.23-1.27(m, 2H),1.71-1.73(d, 3H), 1.78-1.85(m, 1H), 1.90-1.97(m, 1H), 2.40-2.44(m, 2H),2.46-2.58(m, 2H), 2.61-2.67(q, 1H), 2.71-2.75(m, 1H), 4.03-4.09(m, 1H),4.52-4.53(d, 2H), 4.93-5.00(m, 1H), 6.40-6.42(m, 1H), 7.00-7.02(d, 1H),7.11-7.40(m, 12H); LRMS APCI m/z 547 [M+H]⁺

PREPARATION 505-Oxo-5-(4-Phenoxypiperidin-1-yl)-2,2-Diphenylpentanenitrile

1-Hydroxybenzotriazole hydrate (5.67 g, 42 mmol) and triethylamine(14.88 mL, 107 mmol) were added to 4-cyano-4,4-diphenylbutanoic acid(WO97/24325) (10.39 g, 39 mmol) and 4-phenoxy-piperidine hydrochloride(6.32 g, 36 mmol) in N,N-dimethylformamide (150 mL). The mixture wasstirred for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (8.20 g, 42 mmol) was then added and the mixture wasstirred at room temperature for 18 hours. The reaction mixture was thenconcentrated in vacuo and the residue was partitioned between ethylacetate (100 mL) and water (100 mL). The organic layer was separated,washed with water (100 mL) and brine (30 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue was triturated withdiethyl ether, filtered off, washed through with diethyl ether andpurified by column chromatography on silica gel, eluting withpentane:ethyl acetate, 75:25 to 50:50, to afford the title compound as awhite solid (14.4 g) in a 95% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.74-1.90(m, 4H), 2.45-2.49(m, 2H),2.79-2.83(m, 2H), 3.27-3.33(m, 1H), 3.54-3.61(m, 1H), 3.62-3.74(m, 2H),4.49-4.53(m, 1H), 6.87-6.91(m, 2H), 6.93-6.98(m, 1H), 7.26-7.43(m, 12H);LRMS APCI m/z 426 [M+H]⁺

PREPARATION 51 Tert-Butyl 4-[(3-Bromobenzyl)Oxy]Piperidine-1-Carboxylate

Sodium hydride (60% dispersion in mineral oil, 3.31 g, 83 mmol) wasadded to an ice-cooled solution of1-tert-butoxycarbonyl-4-hydroxy-piperidine (16.64 g, 83 mmol) intetrahydrofuran (200 mL) and the mixture was stirred at 0° C. for 30minutes. 3-Bromobenzyl bromide (20.66 g, 83 mmol) was added and themixture was stirred at room temperature for 18 hours. The reaction wasthen quenched with water (50 mL) and concentrated in vacuo. The aqueousresidue was extracted with ethyl acetate (2×100 mL) and the combinedorganic phases were washed with brine (100 mL), dried over magnesiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with pentane:ethyl acetate, 90:10to 80:20, to afford the title compound as a colourless oil in 61% yield,18.64 g.

¹HNMR(400 MHz, CDCl₃) δ: 1.45(s, 9H), 1.54-1.62(m, 2H), 1.81-1.88(m,2H), 3.08-3.14(m, 2H), 3.52-3.58(m, 1H), 3.73-3.79(m, 2H), 4.51(s, 2H),7.18-7.26(m, 2H), 7.38-7.41(m, 1H), 7.49(m, 1H); LRMS APCI m/z 372[M+H]⁺

PREPARATION 52 4-[(3-Bromobenzyl)Oxy]Piperidine

Hydrochloric acid (4M in dioxan, 340 mL) was added to a solution of theproduct of preparation 51 (18.64 g, 50 mmol) in dioxan (50 mL) and themixture was stirred at room temperature for 2.5 hours. The reactionmixture was concentrated in vacuo and the residue was dissolved in 2Maqueous hydrochloric acid (200 mL) and washed with diethyl ether (2×100mL). The aqueous layer was adjusted to pH10 with 2M aqueous sodiumhydroxide solution, extracted with diethyl ether (3×200 mL). Thecombined organic phases were dried over sodium sulfate and concentratedin vacuo to afford the title compound as a colourless oil in 98% yield,13.39 g.

¹HNMR(400 MHz, CDCl₃) δ: 1.45-1.55(m, 2H), 1.92-1.97(m, 2H),2.58-2.64(m, 2H), 3.07-3.13(m, 2H), 3.42-3.49(m, 1H), 4.51(s, 2H),7.17-7.27(m, 2H), 7.37-7.40(m, 1H), 7.50(m, 1H); LRMS APCI m/z 270[M+H]⁺

PREPARATION 535-{4-[(3-Bromobenzyl)Oxy]Piperidin-1-yl}-5-Oxo-2,2-Diphenylpentanenitrile

The title compound was prepared from 4-cyano-4,4-diphenylbutanoic acid(WO9724325) and the product of preparation 52 using the same method asthat described for preparation 50, in 95% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.63(m, 2H), 1.82(m, 2H), 2.46(m, 2H), 2.80(m,2H), 3.17(m, 1H), 3.35(m, 1H), 3.51-3.64(m, 2H), 3.88(m, 1H),4.44-4.53(m, 2H), 7.17-7.42(m, 14H); LRMS APCI m/z 519 [M+H]⁺

PREPARATION 545-(4-Hydroxy-piperidin-1-yl)-5-Methyl-2,2-Diphenyl-Hexanoic Acid Amide

A 1M HCl aqueous solution (9.43 mL, 9.43 mmol) was added to a stirredsolution of example 91 in ethanol (250 mL). 20% Palladium (II) hydroxideon carbon (1 g) was added and the resulting mixture stirred under anatmosphere of hydrogen gas (50 psi) at 50° C. for 18 hours. The reactionmixture was filtered through arbocel and then concentrated in vacuo. Theresidue was dissolved in water (100 mL), the solution adjusted to pH 12with 2M aqueous sodium hydroxide solution and extracted with ethylacetate (3×100 mL). The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo to yield a white foam in 95%yield, 3.39 g.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 6H), 1.23-1.27(m, 2H), 1.39-1.48(m,2H), 1.74-1.78(m, 2H), 2.06-2.11(m, 2H), 2.40-2.44(m, 2H), 2.65-2.68(m,2H), 3.47(m, 1H), 7.23-7.39(m, 10H); LRMS ESI m/z 381 [M+H]⁺

PREPARATION 55 5-Amino-5-Methyl-2,2-Diphenylhexanenitrile

Potassium tert-butoxide (203 mg, 1.81 mmol) and tert-butyl4,4-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide [(400 mg,1.51 mmol), WO2003037327, p 83] were added to a solution ofdiphenylacetonitrile (349 mg, 1.81 mmol) in N,N-dimethylformamide (5 mL)and the mixture was stirred for 18 hours at room temperature. Thereaction mixture was then concentrated in vacuo and the residue wastreated with hydrochloric acid (4M in dioxane, 10 mL) and heated at 40°C. for 2.5 hours. The reaction mixture was concentrated in vacuo and theresidue was basified with saturated sodium hydrogen carbonate solutionand extracted with ethyl acetate (2×30 mL). The combined organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 90:10:1, to afford the titlecompound as a colourless oil in 77% yield, 324 mg.

¹HNMR(400 MHz, CDCl₃) δ: 1.17(m, 6H), 1.48-1.57(m, 2H), 2.20-2.40(brs,2H), 2.42-2.53(m, 2H), 7.22-7.43(m, 10H); LRMS APCI m/z 279 [M+H]⁺

PREPARATION 565-(3-Hydroxyazetidin-1-yl)-5-Methyl-2,2-Diphenylhexanenitrile

A mixture of (+/−)-epichlorohydrin (1.47 mL, 18.76 mmol) and the productof preparation 55 (4.74 g, 17 mmol) in methanol (50 mL) was heated at60° C. for 48 hours. The reaction mixture was then concentrated in vacuoand the residue was partitioned between ethyl acetate (50 mL) and sodiumhydrogen carbonate solution (30 mL). The aqueous layer was separated andextracted with ethyl acetate (2×50 mL). The combined organic solutionwas dried over magnesium sulfate, concentrated in vacuo and the residuewas purified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5, to affordthe title compound as a pale yellow oil in 50% yield, 2.86 g.

¹HNMR(400 MHz, CDCl₃) δ: 0.93(s, 6H), 1.29-1.39(m, 2H), 2.38-2.50(m,2H), 2.90-3.00(m, 2H), 3.29-3.39(m, 2H), 4.29-4.39(m, 1H), 7.24-7.45(m,10H); LRMS APCI m/z 335 [M+H]⁺

PREPARATION 57 1-(4-Cyano-1,1-Dimethyl-4,4-Diphenylbutyl)Azetidin-3-ylmethanesulfonate

Methane sulfonyl chloride (3.3 mL, 43 mmol) was added to a solution ofthe product of preparation 56 (4.82 g, 14.4 mmol) in pyridine (50 mL)cooled to −15° C. The mixture was stirred for 2 hours, allowing thetemperature to warm to 0° C., then concentrated in vacuo. The residuewas partitioned between ethyl acetate (100 mL) and sodium hydrogencarbonate solution (100 mL) and the organic layer was separated, driedover magnesium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography on silica gel, eluting withpentane:ethylacetate/methanol/0.88 ammonia (90/10/1) 2:1, afforded thetitle compound as a yellow oil in 81% yield, 4.80 g.

¹HNMR(400 MHz, CDCl₃) δ: 0.95(s, 6H), 1.30-1.41(m, 2H), 2.42-2.55(m,2H), 2.98(s, 3H), 3.25-3.37(m, 2H), 3.44-3.56(m, 2H), 5.00-5.06(m, 1H),7.23-7.44(m, 10H); LRMS APCI m/z 413 [M+H]⁺

PREPARATION 58 Azetidin-3-yl Methanesulfonate Hydrochloride

A mixture of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate(WO9725322, p 64), (20 g, 63 mmol) and chloroethylchloroformate (10 mL,95 mmol) in dichloromethane (100 mL) was heated under reflux for 2.5hours. The reaction mixture was then concentrated in vacuo and theresidue was re-dissolved in methanol (100 mL) and heated under refluxfor a further 2.5 hours. The mixture was then cooled to room temperatureand concentrated in vacuo to afford the title compound as a white solidin quantitative yield, 9.6 g.

¹HNMR(400 MHz, DMSO-d₆) δ: 3.28(s, 3H), 4.00-4.15(m, 2H), 4.31(m, 2H),5.28-5.38(m, 1H); LRMS APCI m/z 152 [M+H]⁺

PREPARATION 59 4-Cyano-4,4-Diphenylbutanoyl Chloride

N,N-Dimethyltormamide (1 drop) was added to a suspension of4-cyano-4,4-diphenylbutanoic acid [(7.8 g, 29 mmol), WO97/24325] andoxalyl chloride (5.2 mL, 60 mmol) in dichloromethane (40 mL) and themixture was stirred at room temperature for 2 hours. The reactionmixture was then concentrated in vacuo and the residue was azeotropedwith toluene (3×50 mL) to afford the crude title compound. The materialwas used in preparation 60 without further purification.

PREPARATION 60 1-(4-Cyano-4,4-Diphenylbutanoyl)Azetidin-3-ylMethanesulfonate

Triethylamine (12.3 mL, 87 mmol) and a solution of the product ofpreparation 59 (8.23 g, 29 mmol) in dichloromethane were added dropwiseto a solution of preparation 58 (5.53 g, 29 mmol) in dichloromethane (50mL), cooled to −78° C., and the mixture was stirred at this temperaturefor 1 hour. The reaction mixture was quenched with 2N hydrochloric acid(50 mL) and the organic layer was separated, dried over magnesiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with ethyl acetate:pentane, 50:50to 100:0, afforded the title compound as a yellow oil in 97% yield, 11.4g.

¹HNMR(400 MHz, CDCl₃) δ: 2.17-2.29(m, 2H), 2.71-2.80(m, 2H), 3.05(s,3H), 4.03-4.20(m, 2H), 4.26-4.38(m, 2H), 5.18-5.22(m, 1H), 7.24-7.45(m,10H); LRMS APCI m/z 399 [M+H]⁺

PREPARATION 615-{3-[2-(Benzyloxy)Phenoxy]Azetidin-1-yl}-5-Oxo-2,2-Diphenylpentanenitrile

The title compound was prepared from the product of preparation 60 and2-(benzyloxy)phenol, using the same method as that described for example99, as a yellow oil in 77% yield.

¹HNMR(400 MHz, CDCl₃) δ: 2.18-2.24(m, 2H), 2.75-2.80(m, 2H),4.02-4.10(m, 2H), 4.23-4.33(m, 2H), 4.82-4.91(m, 1H), 5.08(s, 2H),6.62-6.65(m, 1H), 6.84-6.99(m, 3H), 7.24-7.43(m, 15H); LRMS APCI m/z 503[M+H]⁺

PREPARATION 625-{3-[2-(Benzyloxy)Phenoxy]Azetidin-1-yl}-5-Methyl-2,2-Diphenylhexanenitrile

A solution of the product of preparation 61 (700 mg, 1.39 mmol) intetrahydrofuran (10 mL) was cooled to −35° C. Zirconium chloride (650 g,2.78 mmol) was added and the reaction mixture was stirred at −35° C. for1 hour. Methyl magnesium chloride (3M in tetrahydrofuran, 4.2 mL, 12.6mmol) was then added dropwise and the mixture was stirred for 3 hours,with the temperature maintained below −20° C. The reaction was quenchedwith 1N sodium hydroxide solution (10 mL) and the mixture was filteredthrough Arbocel®, washing through with ethyl acetate. The organic layerof the filtrate was separated, washed with brine (20 mL), dried overmagnesium sulfate and concentrated in vacuo. Purification of the residueby column chromatography on silica gel, eluting with pentane:ethylacetate, 85:15 to 50:50 afforded the title compound as a yellow oil in10% yield, 69 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.98(s, 6H), 1.35-1.42(m, 2H), 2.45-2.58(m,2H), 3.20-3.32(m, 2H), 3.40-3.55(m, 2H), 4.68-4.78(m, 1H), 5.13(s 2H),6.64-6.72(d, 1H), 6.85-6.99(m, 3H), 7.24-7.48(m, 15H); LRMS ESI m/z 517[M+H]⁺

PREPARATION 635-{3-[2-(Benzyloxy)Phenoxy]Azetidin-1-yl}-5-Methyl-2,2-Diphenylhexanamide

The title compound was prepared from the product of preparation 62,using the same method as that described for example 100, as a colourlessgum in 55% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.90(s, 6H), 1.15-1.22(m, 2H), 2.42-2.52(m,2H), 3.18-3.32(m, 2H), 3.40-3.58(m, 2H), 4.65-4.78(m, 1H), 5.13(s, 2H),5.40-5.60 (m, 2H), 6.62-6.70(m, 1H), 6.82-6.97(m, 3H), 7.23-7.44(m,15H); LRMS APCI m/z 535 [M+H]⁺

PREPARATION 64 3-Phenoxyazetidine Hydrochloride

10% Pd/C (2.5 g) was added to a solution of1-(diphenylmethyl)-3-phenoxy-azetidine (27.7 g, 88 mmol) in ethanol (100mL) and acetic acid (100 mL) and the mixture was stirred at roomtemperature, under 500 psi of hydrogen, for 24 hours. The reactionmixture was then filtered through Arbocel® and the filtrate wasconcentrated in vacuo. The residue was dissolved in diethyl ether (200mL), cooled to 0° C. and treated with hydrochloric acid (1M in diethylether, 120 mL). The solvent was then evaporated under reduced pressureand the residue was azeotroped with toluene and triturated with ethylacetate to afford the title compound as a white solid in 86% yield,13.99 g.

LRMS APCI m/z 160 [M+H]⁺

PREPARATION 655-Oxo-5-(3-Phenoxyazetidin-1-yl)-2,2-Diphenylpentanenitrile

A mixture of the product of preparation 64 (1.13 g, 7.6 mmol),4-cyano-4,4-diphenylbutanoic acid [(2.4 g, 9.12 mmol), WO97/24325],1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.76 g,9.12 mmol), 1-hydroxybenzotriazole hydrate (1.30 g, 9.12 mmol) andN,N-diisopropylethylamine (5.3 mL, 19 mmol) in dichloromethane (50 mL)was stirred at room temperature for 18 hours. The reaction mixture wasthen diluted with ethyl acetate (50 mL), washed with 2M hydrochloricacid (30 mL), and sodium hydrogen carbonate solution (30 mL), dried overmagnesium sulfate and concentrated in vacuo. Purification of the residueby column chromatography on silica gel, eluting with pentane:ethylacetate, 100:0 to 0:100, then afforded the title compound as acolourless oil in 75% yield, 2.28 g.

¹HNMR(400 MHz, CDCl₃) δ: 2.20-2.25(m, 2H), 2.75-2.82(m, 2H),3.97-4.08(m, 2H), 4.28-4.40(m, 2H), 4.85-4.90(m, 1H), 6.65-6.74(m, 2H),6.98-7.04(m, 1H), 7.24-7.43(m, 12H); LRMS APCI m/z 397 [M+H]⁺

PREPARATION 66 Tert-Butyl[4-(Iodomethyl)Phenoxy]Dimethylsilane

Triphenyl phosphine (1.32 g, 5.03 mmol), imidazole (370 mg, 5.47 mmol)and iodine (1.16 g, 4.61 mmol) were added to an ice-cooled solution of4-(tert-butyldimethylsilyloxy)benzyl alcohol [(1 g, 4.19 mmol), Tet.Lett. (2004), 45, 9617] in tetrahydrofuran (50 mL) and the mixture wasstirred at 0° C. for 10 minutes and room temperature for 30 minutes. Thereaction mixture was then concentrated in vacuo and the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated, dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with pentane, afforded the title compound in 41% yield, 600 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.00 (s, 6H), 0.78 (s, 9H), 4.26 (s, 2H),6.72-6.98 (m, 2H), 7.22-7.28 (m, 2H)

PREPARATION 67 5-Allyloxy-2,4-Dichloro-Phenol

4,6-dichlororesorcinol (3.80 g, 21 mmol), allyl bromide (1.82 mL, 21mmol) and potassium carbonate (2.24 g, 21 mmol) were combined in DMF andstirred at room temperature for 18 hours. The DMF was removed in vacuoand the residue acidified with 2M hydrochloric acid (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organic solutionwas dried over magnesium sulphate and concentrated in vacuo. The residuewas purified by column chromatography on silica gel, eluting withpentane:ethyl acetate 9:1 to 4:1 to afford the title compound as ayellow oil in 27% yield, 1.24 g.

¹HNMR(400 MHz, CDCl₃) δ: 4.55-4.60 (m, 2H), 5.33-5.52 (m, 2H), 5.95-6.10(m, 1H), 6.62 (s, 1H), 7.3 (s, 1H); LRMS ESI m/z 217 [M−H]⁺

PREPARATION 685-[3-(5-Allyloxy-2,4-Dichloro-Phenoxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

The title compound was prepared from the products of preparation 67 andpreparation 57, using the same method as that described for example 99,as a colourless gum in 93% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.31-1.40 (m, 2H), 2.41-2.55 (m,2H), 3.20-3.25 (m, 2H), 3.48-3.58 (m, 2H), 4.55-4.58 (m, 2H), 4.62-4.75(m, 1H), 5.32-5.38 (m, 1H), 5.40-5.48 (m, 1H), 5.95-6.10 (m, 1H), 6.28(s, 1H), 7-25-7.45 (m, 11H); LRMS APCI m/z 535 [M+H]⁺

PREPARATION 69 2-Allyloxy-4,5-Dichloro-Phenol

The title compound was prepared from 4,5-dichlorocatechol using the samemethod as that described for preparation 67, as a pink solid in 62%yield.

¹HNMR(400 MHz, CDCl₃) δ: 4.55-4.60 (m, 2H), 5.35-5.45 (m, 2H), 5.81 (1H,s), 5.95-6.10(m, 1H), 6.90 (s, 1H), 7.03 (s, 1H); LRMS APCI m/z 217[M−H]⁺

PREPARATION 705-[3-(2-Allyloxy-4,5-Dichloro-Phenoxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

The title compound was prepared from the products of preparation 69 andpreparation 57, using the same method as that described for example 99,as a colourless gum in 75% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.31-1.40 (m, 2H), 2.41-2.55 (m,2H), 3.15-3.25 (m, 2H), 3.36-3.50 (m, 2H), 4.50-4.58 (m, 2H), 4.60-4.66(m, 1H), 5.28-5.42 (m, 2H), 5.95-6.10 (m, 1H), 6.65 (s, 1H), 6.95 (s,1H), 7-25-7.45 (m, 10H); LRMS APCI m/z 535 [M+H]⁺

PREPARATION 71 1-Allyloxy-3-Bromomethyl-Benzene

To a solution of (3-allyloxy-phenyl)-methanol (Tetrahedron (2000),56(13), 1873-1882) (1.07 g, 6.49 mmol) in THF (7 mls) at 3° C. was addedcarbon tetrabromide (2.69 g, 8.11 mmol) then triphenylphosphine (2.13 g,8.11 mmol) in THF (2 mls). The reaction mixture was stirred at 5° C. for1 hour. The reaction mixture was filtered and concentrated in vacuo. Theresidue was washed with pentane to give a yellow solid which waspurified by column chromatography on silica gel, eluting withpentane:ethyl acetate, 100:0, to 95:5 to afford the title compound as apale yellow oil in 24% yield, 350 mg.

¹HNMR(400 MHz, CDCl₃) δ: 4.47 (s, 2H), 4.51-4.60 (m, 2H), 5.26-5.35 (m,1H), 5.37-5.47 (m, 1H), 5.99-6.11 (m, 1H), 6.82-6.90 (m, 1H), 6.92-7.01(m, 2H), 7.21-7.30 (m, 1H).

PREPARATION 725-[3-(3-Allyloxy-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.596 mmol) wasadded portionwise to an ice-cooled solution of the product ofpreparation 56 (166 mg, 0.496 mmol) in N,N-dimethylformamide (2 mL) andthe mixture was stirred at 0° C. for 15 mins. The product of preparation71 (169 mg, 0.746 mmol) was added and the mixture was stirred for 0.5hour at 0° C. The reaction mixture was then quenched with 2Nhydrochloric acid (2 mL) then basified with saturated sodium hydrogencarbonate solution. The resulting mixture was then partitioned betweenethyl acetate (50 mL) and water (10 mL). The aqueous layer was separatedand extracted with ethyl acetate (1×50 mL). The combined organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 100:0:0 to 98:2:0.2 toafford the title compound as a colourless gum in 54% yield, 130 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.93(s, 6H), 1.26-1.38 (m, 2H), 2.38-2.50 (m,2H), 2.96-3.10 (m, 2H), 3.18-3.36 (m, 2H), 4.06-4.18 (m, 1H), 4.39 (s,2H), 4.52-4.58 (m, 2H), 5.25-5.33 (m, 1H), 5.37-5.47 (m, 1H), 6.00-6.11(m, 1H), 6.81-6.93(m, 3H), 7.20-7.45(m, 11H); LRMS APCI m/z 481 [M+H]⁺

PREPARATION 735-Methyl-2,2-Diphenyl-5-[3-(3-Propenyloxy-Benzyloxy)-Azetidin-1-Yl]-HexanoicacidAmide

Potassium hydroxide (303 mg, 5.42 mmol) was added to a solution ofpreparation 72 (130 mg, 0.271 mmol) in 3-methyl-3-pentanol (5 mL) andthe mixture was heated under reflux for 24 hours. The reaction mixturewas then cooled to room temperature, concentrated in vacuo and theresidue was partitioned between ethyl acetate (50 mL) and water (10 mL).The aqueous layer was separated, extracted with ethyl acetate (2×30 mL)and the combined organic solution was dried over magnesium sulfate andconcentrated in vacuo to give a colourless gum in 96% yield, 130 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.87(s, 6H), 1.07-1.19(m, 2H), 1.64-1.76 (m,3H), 2.37-2.47(m, 2H), 2.94-3.10 (m, 2H), 3.20-3.40(m, 2H), 4.08-4.20(m,1H), 4.35 (s, 2H), 4.83-4.93(m, 1H), 5.35-5.65 (d, 2H), 6.34-6.40 (d,1H), 6.88-6.98(m, 3H), 7.20-7.40 (m, 11H); LRMS APCI m/z 499 [M+H]⁺

PREPARATION 74 3-Allyloxy-2,6-Dichloro-Benzaldehyde

2,6-dichloro-3-hydroxybenzaldehyde (960 mg, 5.03 mmol) (Synthesis, 2004,12, 2062), allyl bromide (431 μL, 5.03 mmol) and potassium carbonate(563 mg, 10.06 mmol) were combined in DMF (5 mL) and stirred at roomtemperature for 18 hours. The DMF was removed in vacuo and the residuepartitioned between diethyl ether (50 mL) and water (30 mL). The layerswere separated and the aqueous extracted with diethyl ether (2×30 mL).The combined organic solution was dried over magnesium sulphate andconcentrated in vacuo to afford the title compound as a yellow solidwhich was used without further purification in preparation 75.

¹HNMR(400 MHz, CDCl₃) δ: 4.62-4.65 (m, 2H), 5.35-5.38 (m, 1H), 5.45-5.52(m, 1H), 6.00-6.13 (m, 1H), 7.00-7.04 (m, 1H), 7.27-7.35 (m, 1H), 10.46(s, 1H); LRMS APCI m/z 232 [M+H]⁺

PREPARATION 75 (3-Allyloxy-2,6-Dichloro-Phenyl)-Methanol

The product of preparation 74 (˜5.03 mmol) was dissolved in ethanol (30mL) and sodium borohydride (284 mg, 7.79 mmol) was added. The reactionmixture was stirred at room temperature for 30 minutes. The reaction wasdiluted with water (30 mL) and glacial acetic acid was added dropwiseuntil no further effervescence was observed. The mixture was extractedwith diethyl ether (2×50 mL). The combined organic extracts were washedwith brine, dried over magnesium sulphate and concentrated in vacuo toafford the title compound as a colourless solid which was used withoutfurther purification in preparation 76.

¹HNMR(400 MHz, CDCl₃) δ: 4.54-4.64 (m, 2H), 4.98 (s, 2H), 5.33-5.38 (m,1H), 5.43-5.52 (m, 1H), 5.99-6.11 (m, 1H), 6.83-6.88 (m, 1H), 7.24-7.28(m, 1H).

PREPARATION 76 1-Allyloxy-2,4-Dichloro-3-Chloromethyl-Benzene

The product of preparation 75 (400 mg, 1.72 mmol) was dissolved indichloromethane (20 mL) and thionyl chloride (312 μL, 4.29 mmol) wasadded over 1 minute. The reaction mixture was stirred at roomtemperature for 10 minutes. The reaction was quenched with water (2×10mL). The organic layer was dried over magnesium sulphate andconcentrated in vacuo to afford the title compound as a yellow solid in91% yield (390 mg)

¹HNMR(400 MHz, CDCl₃) δ: 4.54-4.64 (m, 2H), 4.88 (s, 2H), 5.28-5.37 (m,1H), 5.42-5.50 (m, 1H), 5.99-6.11 (m, 1H), 6.83-6.91 (m, 1H), 7.24-7.33(m, 1H).

PREPARATION 775-[3-(3-Allyloxy-2,6-Dichloro-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

Sodium hydride (60% dispersion in mineral oil, 25 mg, 0.629 mmol) wasadded portionwise to an ice-cooled solution of the product ofpreparation 56 (140 mg, 0.419 mmol) in N,N-dimethylformamide (2 mL) andthe mixture was stirred at 0° C. for 30 mins. The product of preparation76 (137 mg, 0.546 mmol) was added in DMF (1 mL) and the mixture wasstirred for 18 hour at room temperature. The reaction mixture was thenquenched saturated sodium hydrogen carbonate solution (10 mL) and theresulting mixture was extracted with diethyl ether (3×50 mL). Thecombined organic solution was dried over magnesium sulfate, concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to98:2:0.2 to afford the title compound as a colourless gum in 87% yield,200 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.28-1.38 (m, 2H), 2.40-2.48 (m,2H), 3.00-3.10 (m, 2H), 3.20-3.38 (m, 2H), 4.15-4.25 (m, 1H), 4.58-4.62(m, 2H), 4.68 (s, 2H), 5.26-5.35 (m, 1H), 5.42-5.48 (m, 1H), 6.00-6.08(m, 1H), 6.82-6.85 (m, 1H), 7.21-7.44 (m, 11H); LRMS APCI m/z 549 [M+H]⁺

PREPARATION 785-(3-{2,6-Dichloro-3-[((E)-Propenyl)Oxy]-Benzyloxy}-Azetidin-1-Yl)-5-Methyl-2,2-Diphenyl-HexanoicAcid Amide

Potassium hydroxide (400 mg, 7.14 mmol) was added to a solution ofpreparation 77 (200 mg, 0.364 mmol) in 3-methyl-3-pentanol (3 mL) andthe mixture was heated at 120° C. for 24 hours. The reaction mixture wasthen cooled to room temperature, concentrated in vacuo and the residuewas partitioned between ethyl acetate (50 mL) and water (30 mL). Theaqueous layer was separated, extracted with ethyl acetate (2×50 mL) andthe combined organic solution was dried over magnesium sulfate andconcentrated in vacuo. Recrystallisation from diisopropylether gave thetitle compound as a colourless solid in 73% yield, 150 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.90 (s, 6H), 1.12-1.20 (m, 2H), 1.72-1.78 (m,3H), 2.40-2.52 (m, 2H), 3.02-3.15 (m, 2H), 3.24-3.40 (m, 2H), 4.15-4.25(m, 1H), 4.68 (s, 2H), 4.98-5.07 (m, 1H), 5.35-5.63 (br m, 2H),6.25-6.28 (m, 1H), 6.92-6.95 (m, 1H), 7.21-7.38 (m, 11H); LRMS ESI m/z567 [M+H]⁺

PREPARATION 79 Sulfamic acid 2-Cyclopentyl-Ethyl Ester

To chlorosulfonyl isocyanate (275 mL, 3.15 mol) at 0° C. was addedformic acid (119 mL, 3.15 mol), dropwise. The resulting solid wasallowed to stir at 0° C. for a further 20 minutes. The residue wasdiluted with dichloromethane (875 mL) and warmed to room temperature forone hour. The reaction mixture was cooled in an ice/salt bath and asolution of 2-cyclopentyl ethanol (240 g, 2.1 mol) in pyridine (255 mL,3.15 mol) and dichloromethane (2.1 L) was added, keeping the temperaturebelow 7° C. After 2 hours, the reaction was concentrated in vacuo,diluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and brine. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo to give a colourless oil. The residuewas purified by column chromatography on silica gel, eluting with 90:10to 50:50 heptane:ethyl acetate, to afford the title compound as acolourless oil in 95% yield (276 g).

PREPARATION 80 8-Oxa-7-Thia-6-Aza-Spiro[4.5]Decane 7,7-Dioxide

To the product of preparation 79 (276 g, 1.43 mol) in dichloromethane(7.1 L) at room temperature were added magnesium oxide (132.5 g, 3.29mol), iodobenzene diacetate (507 g, 1.57 mol) and rhodium acetate dimer(12.6 g, 0.028 mol). The reaction mixture was stirred at roomtemperature for 18 hours. The residue was filtered through a bed ofcelite and the solvent was removed in vacuo. The residue was purified bycolumn chromatography on silica gel, eluting with 90:10 to 50:50heptane:ethyl acetate, to afford the title compound as a whitecrystalline solid in 75% yield (205 g).

¹HNMR(400 MHz, CDCl₃) δ: 1.63-1.78 (m, 4H), 1.79-2.00 (m, 4H), 2.00-2.11(m, 2H), 4.64-4.67 (m, 2H), 4.71 (s, 1H); LRMS APCI m/z 214 [M+Na]⁺

PREPARATION 817,7-Dioxo-8-Oxa-7Lambda*6*-Thia-6-Aza-Spiro[4.5]decane-6-carboxylic acidtert-butylester

The product of preparation 80 (1.0 g, 5.23 mmol), di-tert-butyldicarbonate (1.36 g, 6.24 mmol), triethyamine (1.06 g, 10.5 mmol) and4-dimethylaminopyridine (126 mg, 1.03 mmol) were combined at roomtemperature in dichloromethane (50 mL). After 3 hours, the reaction waswashed with ammonium chloride (50 mL, sat. aq.) and the organic solutionwas dried over magnesium sulfate and concentrated in vacuo. The residuewas purified by column chromatography on silica gel, eluting with 100:0to 80:20 pentane:ethyl acetate, to afford the title compound as acolourless oil in 46% yield (700 mg).

¹HNMR(400 MHz, CDCl₃) δ: 1.48 (s, 9H), 1.48-1.66 (m, 2H), 1.82-1.96 (m,4H), 2.17-2.33 (m, 4H), 4.57-4.63 (m, 2H).

PREPARATION 82 4-(1-Amino-Cyclopentyl)-2,2-Diphenyl-Butyronitrile

The title compound was prepared from the product of preparation 81 usinga similar method to that described for preparation 55, in 67% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.43-1.58 (m, 4H), 1.58-1.67 (m, 4H), 1.72-1.80(m, 2H), 2.49-2.60 (m, 2H), 7.25-7.46 (m, 10H); LRMS APCI m/z 305 [M+H]⁺

PREPARATION 834-[1-(3-Hydroxy-Azetidin-1-yl)-Cyclopentyl]-2,2-Diphenyl-Butyronitrile

The title compound was prepared from the product of preparation 82 usinga similar method to that described for preparation 56, in 52% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.25-1.38 (m, 2H), 1.39-1.64 (m, 6H), 1.65-1.78(m, 2H), 2.42-2.55 (m, 2H), 2.86-2.97 (m, 2H), 3.36-3.40 (m, 2H),4.29-4.40 (m, 1H), 7.25-7.48 (m, 10H); LRMS APCI m/z 361 [M+H]⁺

PREPARATION 84 Methanesulfonic Acid1-[1-(3-Cyano-3,3-Diphenyl-Propyl)-Cyclopentyl]-Azetidin-3-yl Ester

The title compound was prepared from the product of preparation 83 usinga similar method to that described for preparation 57, in 59% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.25-1.67 (m, 10H), 2.42-2.52 (m, 2H), 3.00 (s,3H), 3.15-3.26 (m, 2H), 3.40-3.55 (m, 2H), 4.95-5.05 (m, 1H), 7.27-7.45(m, 10H); LRMS APCI m/z 439 [M+H]⁺

PREPARATION 855-[3-(3-Allyloxy-4-Chloro-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

The title compound was prepared from the product of preparation 56 andthe product of preparation 42 using a similar method to that describedfor example 101, in 83% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.32-1.38 (m, 2H), 2.40-2.48 (m,2H), 2.97-3.06 (m, 2H), 3.23-3.32 (m, 2H), 4.05-4.16 (m, 1H), 4.36 (s,2H), 4.58-4.65 (m, 2H), 5.28-5.35 (m, 1H), 5.43-5.63 (m, 1H), 6.02-6.16(m, 1H), 6.80-6.85 (m, 1H), 6.92 (s, 1H), 7.23-7.42 (m, 11H); LRMS APCIm/z 515 [M+H]⁺

PREPARATION 865-(3-{4-Chloro-3-[((E)-Propenyl)Oxy]-Benzyloxy}-Azetidin-1-yl)-5-Methyl-2,2-Diphenyl-Hexanoicacid amide

The title compound was prepared from the product of preparation 85 usinga similar method to that described for preparation 73, in 75% yield.

LRMS APCI m/z 533 [M+H]⁺

PREPARATION 874-{1-[3-(3-Allyloxy-4-Chloro-Phenoxy)-Azetidin-1-Yl]-Cyclopentyl}-2,2-Diphenyl-Butyronitrile

The title compound was prepared from the product of preparation 84 and3-allyloxy-4-chlorophenol (EP78099) using a similar method to thatdescribed for example 99, in 82% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.25-1.40 (m, 2H), 1.40-1.65 (m, 6H), 1.66-1.77(m, 2H), 2.46-2.58 (m, 2H), 3.07-3.16 (m, 2H), 3.46-3.58 (m, 2H),4.55-4.59 (m, 2H), 4.60-4.73 (m, 1H), 5.26-5.35 (m, 1H), 5.43-5.53 (m,1H), 6.00-6.13 (m, 1H), 6.20-6.28 (m, 1H), 6.42 (s, 1H), 7.19-7.23 (m,1H), 7.23-7.46 (m, 10H); LRMS APCI m/z 527 [M+H]⁺

PREPARATION 884-[1-(3-{4-Chloro-3-[((E)-Propenyl)Oxy]-Phenoxyl}-Azetidin-1-Yl)-Cyclopentyl]-2,2-Diphenyl-Butyramide

The title compound was prepared from the product of preparation 87 usinga similar method to that described for preparation 73, in 49% yield.

LRMS APCI m/z 545 [M+H]⁺

PREPARATION 89 3-Bromo-5-Methoxy-Phenol

1-bromo-3,5-dimethyoxybenzene (3.0 g, 13.8 mmol) was dissolved indichloromethane (45 mL) and the solution was cooled to −78° C. Borontribromide (1M in dichloromethane, 41 mL, 41 mmol) was added and thesolution was warmed gradually to room temperature over 18 hours. Aftercooling to −78° C., the reaction was quenched with water (100 mL). Theorganics were separated and washed with sodium thiosulphate solutionthen water, then dried over magnesium sulfate and concentrated in vacuo.The residue was purified by column chromatography on silica gel, elutingwith pentane:ethyl acetate 100:0 to 80:20, to afford the title compoundin 16% yield (470 mg).

¹HNMR(400 MHz, MeOD) δ: 3.76 (s, 3H), 6.28 (s, 1H), 6.53-6.57(m, 2H).

PREPARATION 90 4-Allyloxy-3-Chloro-Benzaldehyde

The title compound was prepared from 3-chloro-4-hydroxybenzaldehydeusing a similar method to that described for preparation 74, in 96%yield. The material was used without further purification in preparation91.

¹HNMR(400 MHz, CDCl₃) δ: 4.68-4.76 (m, 2H), 5.35-5.39 (m, 1H), 5.44-5.56(m, 1H), 6.02-6.15 (m, 1H), 7.01-7.05 (m, 1H), 7.76-7.79 (m, 1H), 7.93(s, 1H), 9.86 (s, 1H); LRMS APCI m/z 197 [M+H]⁺

PREPARATION 91 (4-Allyloxy-3-Chloro-Phenyl)-Methanol

The title compound was prepared from the product of preparation 90 usinga similar method to that described for preparation 75, in 100% yield.The material was used without further purification in preparation 92.

¹HNMR(400 MHz, CDCl₃) δ: 4.61-4.65 (m, 4H), 5.28-5.36 (m, 1H), 5.44-5.52(m, 1H), 6.02-6.13 (m, 1H), 6.88-6.94 (m, 1H), 7.17-7.20 (m, 1H), 7.40(s, 1H).

PREPARATION 92 1-Allyloxy-2-Chloro-4-Chloromethyl-Benzene

The title compound was prepared from the product of preparation 91 usinga similar method to that described for preparation 76, in 70% yield. Thematerial was used without further purification in preparation 94.

¹HNMR(400 MHz, CDCl₃) δ: 4.52 (s, 2H), 4.60-4.63 (m, 2H), 5.28-5.35 (m,1H), 5.43-5.54 (m, 1H), 6.01-6.12 (m, 1H), 6.86-6.94 (m, 1H), 7.20-7.24(m, 1H), 7.42 (s, 1H).

PREPARATION 935-(3-Hydroxy-Azetidin-1-Yl)-5-Methyl-2,2-Diphenyl-Hexanoic Acid Amide

The product from example 102 (5.2 g, 12.2 mmol), ammonium formate (4.25g, 92 mmol) and palladium hydroxide 20 wt % Pd on carbon (1.7 g) werecombined in ethanol (150 mL) and stirred at reflux for one hour. Aftercooling, the residue was filtered through Arbocel®, washing with MeOH(50 mL). The filtrate was concentrated in vacuo. The residue was dilutedwith ethyl acetate (100 mL) and washed with sodium hydrogen carbonatesolution (30 mL, sat. aq.). The organic extract was dried over magnesiumsulfate and concentrated in vacuo. The title compound was isolated as acolourless foam in 97% yield, 4.2 g.

¹HNMR(400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.08-1.18 (m, 2H), 2.35-2.45 (m,2H), 2.85-2.95 (m, 2H), 3.26-3.35 (m, 2H), 4.25-4.35 (m, 1H), 5.56-5.80(br m, 2H), 7.15-7.40 (m, 10H); LRMS ESI m/z 353 [M+H]⁺

PREPARATION 945-[3-(4-Allyloxy-3-chloro-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-HexanoicAcid Amide

The product of preparation 93 (300 mg, 0.85 mmol) was dissolved in DMFat 0° C. (5 mL) and sodium hydride (60% dispersion in oil, 62 mg, 1.6mmol) added. After 30 minutes, a solution of the product of preparation92 (210 mg, 1.15 mmol) in DMF (1 mL) was added. After 30 minutes, thereaction was quenched with 2N HCl (20 ml), basified with saturatedsodium hydrogen carbonate and the product extracted with ethyl acetate(20 mL). The organic extract was dried over magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 100:0:0 to 90:10:1, afforded the title compound as a colourlessoil in 22% yield, 100 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.11-1.20 (m, 2H), 2.39-2.47 (m,2H), 2.98-3.08 (m, 2H), 3.23-3.39 (m, 2H), 4.08-4.17 (m, 1H), 4.28 (s,2H), 4.58-4.63 (m, 2H), 5.27-5.35 (m, 1H), 5.45-5.50 (m, 1H), 5.40-5.60(br m, 2H), 6.01-6.13 (m, 1H), 6.85-6.92 (m, 1H), 7.07-7.15 (m, 1H),7.20-7.37 (m, 11H); LRMS ESI m/z 533 [M+H]⁺

PREPARATION 95 2-Allyloxy-4-Chloro-Benzaldehyde

The title compound was prepare from 4-chloro-2-hydroxybenzaldehyde usinga similar method to that described for preparation 74, in 85% yield. Thematerial was used without further purification in preparation 96.

¹HNMR(400 MHz, CDCl₃) δ: 4.62-4.66 (m, 2H), 5.35-5.39 (m, 1H), 5.40-5.46(m, 1H), 6.02-6.13 (m, 1H), 6.92-6.96 (m, 1H), 7.45-7.51 (m, 1H), 7.80(s, 1H), 10.45 (s, 1H); LRMS APCI m/z 197 [M+H]⁺

PREPARATION 96 (2-Allyloxy-4-Chloro-Phenyl)-Methanol

The title compound was prepared from the product of preparation 95 usinga similar method to that described for preparation 75, in 100% yield.The material was used without further purification in preparation 97.

¹HNMR(400 MHz, CDCl₃) δ: 4.55-4.60 (m, 2H), 4.67 (s, 2H), 5.28-5.35 (m,1H), 5.38-5.45 (m, 1H), 5.98-6.08 (m, 1H), 6.76-6.83 (m, 1H), 7.17-7.21(m, 1H), 7.33 (s, 1H).

PREPARATION 97 2-Allyloxy-4-Chloro-1-Chloromethyl-Benzene

The title compound was prepared from the product of preparation 96 usinga similar method to that described for preparation 76, in 77% yield. Thematerial was used without further purification in preparation 98

¹HNMR(400 MHz, CDCl₃) δ: 4.57-4.60 (m, 2H), 4.62 (s, 2H), 5.28-5.35 (m,1H), 5.40-5.47 (m, 1H), 6.00-6.09 (m, 1H), 6.78-6.83 (m, 1H), 7.20-7.25(m, 1H), 7.37 (s, 1H).

PREPARATION 985-[3-(2-Allyloxy-4-Chloro-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-HexanoicAcid Amide

The title compound was prepared from the products of preparation 97 and93 using a similar method to that described for preparation 94, in 18%yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.10-1.98 (m, 2H), 2.38-2.45 (m,2H), 2.98-3.08 (m, 2H), 3.28-3.39 (m, 2H), 4.10-4.20 (m, 1H), 4.40 (s,2H), 4.47-4.55 (m, 2H), 5.23-5.32 (m, 1H), 5.35-5.41 (m, 1H), 5.53-5.86(br m, 2H), 5.97-6.08 (m, 1H), 6.73-6.78 (m, 1H), 7.14-7.20 (m, 1H),7.20-7.39 (m, 11H); LRMS ESI m/z 533 [M+H]⁺

PREPARATION 99 3-Allyloxy-2-Chloro-Benzaldehyde

The title compound was prepared from 2-chloro-3-hydroxybenzaldehydeusing a similar method to that described for preparation 74, in 100%yield. The material was used without further purification in preparation100.

PREPARATION 100 (3-Allyloxy-2-Chloro-Phenyl)-Methanol

The title compound was prepared from the product of preparation 99 usinga similar method to that described for preparation 31, in 92% yield. Thematerial was used without further purification in preparation 101.

¹HNMR(400 MHz, CDCl₃) δ: 4.62-4.66 (m, 2H), 4.78 (s, 2H), 5.32-5.37 (m,1H), 5.46-5.52 (m, 1H), 6.02-6.15 (m, 1H), 6.86-6.94 (m, 1H), 7.07-7.14(m, 1H), 7.20-7.28 (m, 1H).

PREPARATION 101 1-Allyloxy-2-Chloro-3-Chloromethyl-Benzene

The product of preparation 100 (740 mg, 3.73 mmol) was dissolved indichloromethane (20 mL) and thionyl chloride (678 μL, 9.32 mmol) wasadded over 1 minute. The reaction mixture was stirred at roomtemperature for 2 hours. A further 600 μl thionyl chloride was added andthe reaction stirred for 1 hour. The reaction was quenched with water(10 mL). The organic layer was washed with saturated sodium hydrogencarbonate solution (20 mL) and water (10 mL), dried over magnesiumsulphate and concentrated in vacuo. Purification of the residue bycolumn chromatography on silica gel, eluting with pentane:ethyl acetate100:0 to 99:1 afforded the title compound as a colourless oil in 21%yield, 168 mg.

¹HNMR(400 MHz, CDCl₃) δ: 4.59-4.68 (m, 2H), 4.75 (s, 2H), 5.28-5.37 (m,1H), 5.44-5.55 (m, 1H), 6.00-6.15 (m, 1H), 6.86-6.95 (m, 1H), 7.06-7.13(m, 1H), 7.17-7.26 (m, 1H).

PREPARATION 1025-[3-(3-Allyloxy-2-Chloro-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

The title compound was prepared from the products of preparations 101and 56 using a similar method to that described for example 101, in 69%yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.29-1.38 (m, 2H), 2.40-2.52 (m,2H), 3.02-3.15 cm, 2H), 3.24-3.39 (m, 2H), 4.15-4.22 (m, 1H), 4.53 (s,2H), 4.60-4.64 (m, 2H), 5.28-5.35 (m, 1H), 5.45-5.50 (m, 1H), 6.03-6.15(m, 1H), 6.86-6.90 (m, 1H), 7.05-7.08 (m, 1H), 7.16-7.23 (m, 1H),7.23-7.45 (m, 10H); LRMS APCI m/z 515 [M+H]⁺

PREPARATION 1035-(3-{2-Chloro-3-[((E)-Propenyl)Oxy]-Benzyloxy}-Azetidin-1-Yl)-5-Methyl-2,2-Diphenyl-Hexanoicacid amide

The title compound was prepared from the product of preparation 102using a similar method to that described for preparation 78, in 61%yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.19-1.20 (m, 2H), 1.72-1.78 (m,3H), 2.40-2.48 (m, 2H), 3.02-3.15 (m, 2H), 3.20-3.42 (m, 2H), 4.13-4.25(m, 1H), 4.53 (s, 2H), 4.95-5.03 (m, 1H), 5.32-5.60 (br m, 2H),6.30-6.45 (m, 1H), 6.93-6.97 (m, 1H), 7.12-7.40 (m, 12H); LRMS ESI m/z533 [M+H]⁺

PREPARATION 104 Methanesulfonic Acid1-(4-Carbamoyl-1,1-Dimethyl-4,4-Diphenyl-Butyl)-Azetidin-3-Yl Ester

Methane sulfonyl chloride (102 μL, 1.33 mmol) was added dropwise to asolution of the product of preparation 93 (156 mg, 0.44 mmol) inpyridine (5 mL), cooled to −20° C. The mixture was warmed gradually to5° C. over 2 hours. Saturated sodium hydrogen carbonate solution (10 mL)was added and the reaction mixture stirred at room temperature for 10minutes. The residue was extracted with ethyl acetate (3×30 mL) and thecombined organics were dried over magnesium sulphate, filtered andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting withpentane:ethylacetate/methanol/0.88 ammonia (90/10/1) 8:1 to 1:2,afforded the title compound as a colourless oil in 74% yield, 142 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.88 (s, 6H), 1.08-1.15 (m, 2H), 2.38-2.45 (m,2H), 2.98 (s, 3H), 3.07-3.22 (m, 2H), 3.36-3.52 (m, 2H), 4.95-5.00 (m,1H), 5.42-5.53 (br m, 1H), 5.71-5.80 (br m, 1H), 7.23-7.38 (m, 10H);LRMS ESI m/z 431 [M+H]⁺

PREPARATION 1055-[3-(3-Benzyloxy-Phenoxy)-Azetidin-1-Yl]-5-Methyl-2,2-Diphenyl-Hexanenitrile

The title compound was prepared from the product of preparation 57 and3-(benzyloxy)phenol, using the same method as that described in example99, as a yellow oil in 95% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.35-1.42 (m, 2H), 2.40-2.52 (m,2H), 3.09-3.20 (m, 2H), 3.40-3.52 (m, 2H), 4.61-4.72 (m, 1H), 5.06 (s,2H), 6.36-6.40 (m, 2H), 6.57-6.62 (m, 1H), 7.10-7.18 (m, 1H), 7.15-7.47(m, 15H); LRMS APCI m/z 517 [M+H]⁺

PREPARATION 106 (4-Allyloxy-Phenyl)-Methanol

The title compound was prepared from the 4-hydroxybenzyl alcohol using asimilar method to that described for preparation 74, in 57% yield.

¹HNMR(400 MHz, CDCl₃) δ: 4.52-4.94 (m, 2H), 4.63 (s, 2H), 5.28-5.35 (m,1H), 5.38-5.45 (m, 1H), 6.00-6.12 (m, 1H), 6.86-6.94 (m, 2H), 7.24-7.33(m, 2H).

PREPARATION 107 1-Allyloxy-4-Chloromethyl-Benzene

The title compound was prepared from the product of preparation 106using a similar method to that described for preparation 76 in 43%yield.

¹HNMR(400 MHz, CDCl₃) δ: 4.53-4.58 (m, 4H), 5.25-5.32 (m, 1H), 5.36-5.43(m, 1H), 6.00-6.12 (m, 1H), 6.86-6.94 (m, 2H), 7.28-7.35 (m, 2H)

PREPARATION 1085-[3-(4-Allyloxy-Benzyloxy)-Azetidin-1-yl]-5-Methyl-2,2-Diphenyl-HexanoicAcid Amide

The title compound was prepared from the products of preparations 107and 93 using a similar method to that described for preparation 94, in25% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.24-1.28 (m, 2H), 2.35-2.45 (m,2H), 2.94-3.00 (m, 2H), 3.20-3.28 (m, 2H), 4.05-4.15 (m, 1H), 4.35 (s,2H), 4.52-4.55 (m, 2H), 5.25-5.28 (m, 1H), 5.36-5.43 (m, 1H), 5.40-5.60(br m, 2H), 6.00, 6.12 (m, 1H), 6.84-6.89 (m, 2H), 7.20-7.38 (m, 12H);LRMS APCI m/z 499 [M+H]⁺

EXAMPLE 15-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanenitrile

A solution of the product of preparation 11 (3.31 g, 8.07 mmol) intetrahydrofuran 190 mL) was cooled to −20° C. Zirconium chloride (3.76g, 16.15 mmol) was added and the reaction mixture was stirred at −20° C.for 1 hour. Methyl magnesium chloride (3M in tetrahydrofuran, 24 mL, 72mmol) was then added dropwise and the mixture was stirred for 2 hours,with the temperature maintained below −10° C. The reaction was quenchedwith 1M aqueous sodium hydroxide solution (25 mL) and then filteredthrough Celite®, washing through with ethyl acetate (2×50 mL). Thefiltrate was washed with brine (70 mL), concentrated in vacuo and theresidue was re-crystallised from hexane/ethyl acetate to afford thetitle compound as a pale orange crystalline solid in 59% yield, 2 g.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.23-1.27(m, 2H),1.85-1.93(m, 1H), 2.07-2.16(m, 1H), 2.40-2.45(m, 2H), 2.58-2.67(m, 2H),2.72-2.78(m, 1H), 2.87-2.91(m, 1H), 4.75-4.79(m, 1H), 6.80(d, 2H),6.88-6.92(m, 1H), 7.21-7.36(m, 12H); LRMS APCI m/z 425 [M+H]⁺

EXAMPLE 25-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide

Potassium hydroxide (5.10 g, 91.98 mmol) was added to a solution of theproduct of example 1 (1.959, 4.60 mmol) in 3-methyl-3-pentanol (40 mL)and the mixture was heated under reflux for 24 hours. The reactionmixture was then cooled to room temperature, concentrated in vacuo andthe residue was partitioned between ethyl acetate (70 mL) and water (40mL). The aqueous layer was separated, extracted with ethyl acetate (50mL) and the combined organic solution was dried over sodium sulfate andconcentrated in vacuo. The residue was then re-crystallised fromhexane/ethyl acetate and dried under vacuum for 18 hours to afford thetitle compound as a white solid in 82% yield, 1.66 g.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.02(s, 3H), 1.19-1.33(m, 2H),1.82-1.91(m, 1H), 2.02-2.17(m, 1H), 2.37-2.47(m, 2H), 2.48-2.64(m, 2H),2.65-2.75(m, 1H), 2.81-2.89(m, 1H), 4.75(m, 1H), 6.76-6.83(m, 2H),6.86-6.92(m, 1H), 7.17-7.38(m, 12H); LRMS APCI m/z 425 [M+H]⁺

EXAMPLE 35-Methyl-5-[(3R)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanenitrile

A solution of the product of preparation 12 (0.84 g, 2.05 mmol) intetrahydrofuran (15 mL) was cooled to −10° C. Titanium (IV) chloride(0.23 mL, 2.05 mmol) was added and the reaction mixture was stirred at−10° C. for 15 minutes. Methyl magnesium bromide (3M, in diethyl ether,4.1 mL, 12.3 mmol) was then added dropwise and the mixture was stirredfor 10 minutes at temperatures below −5° C. and at room temperature for18 hours. The reaction mixture was slowly quenched with water (4 mL),diluted with ethyl acetate (20 mL) and then decanted off. The residualsolid was extracted with ethyl acetate (3×20 mL) and the combinedorganic solution was dried over sodium sulphate and concentrated invacuo. Purification of the residue by column chromatography on silicagel, eluting with ethyl acetate:hexane, 60:40, afforded the titlecompound in 54% yield, 0.47 g.

LRMS APCI m/z 425 [M+H]⁺

EXAMPLE 45-Methyl-5-[(3R)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide

The title compound was prepared from the product of example 3, using thesame method as that described for example 2, in 62% yield.

LRMS APCI m/z 443 [M+H]⁺

EXAMPLE 55-[(3S)-3-(3-Methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of preparation 13,using the same method as that described for example 1. The crudecompound was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 97.5:2.5:0.25 to 95:5:0.5,to afford the desired product as a brown oil in 78% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.01(s, 3H), 1.07(s, 3H), 1.43-1.47(m, 2H),1.86-1.93(m, 1H), 2.08-2.19(m, 1H), 2.47-2.59(m, 3H), 2.65-2.69(m, 1H),2.73-2.86(m, 2H), 3.73(s, 3H), 4.74-4.79(m, 1H), 6.38-6.43(m, 2H),6.47-6.50(m, 1H), 7.11-7.15(m, 1H), 7.24-7.42(m, 10H); LRMS APCI m/z 456[M+H]⁺

EXAMPLE 65-[(3S)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 5, using thesame method as that described for example 2, as a pale yellow gum in 96%yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.08(s, 3H), 1.24-1.30(m, 2H),1.89-1.98(m, 1H), 2.08-2.16(m, 1H), 2.40-2.46(m, 2H), 2.65-2.76(m, 2H),2.79-2.88(m, 1H), 2.91-2.98(m, 1H), 3.74(s, 3H), 4.77-4.82(m, 1H),6.37-6.42(m, 2H), 6.51(dd, 1H), 7.12-7.16(m, 1H), 7.22-7.36(m, 10H);LRMS APCI m/z 474 [M+H]⁺

EXAMPLE 75-[(3S)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 20.7 mL, 20.7 mmol) was addedto an ice-cooled solution of the product of example 6 (2.45 g, 5.18mmol) in dichloromethane (25 mL) and the mixture was stirred at 0° C.for 20 minutes. The reaction was then quenched with 0.88 ammoniasolution and stirred at room temperature for 20 minutes. The reactionmixture was extracted with dichloromethane (3×25 mL) and the combinedorganic solution was dried over sodium sulfate and concentrated invacuo. Purification of the residue by column chromatography on silicagel, eluting with pentane:ethyl acetate/methanol/0.88 ammonia (90:10:1),50:50 to 33:66, afforded the title compound as a white foam in 60%yield, 1.42 g.

¹HNMR(400 MHz, CD₃OD) δ: 1.06(s, 3H), 1.11(s, 3H), 1.30-1.34(m, 2H),1.94-2.01(m, 1H), 2.08-2.17(m, 1H), 2.42-2.46(m, 2H), 2.77-2.93(m, 3H),2.99-3.05(m, 1H), 4.79(m, 1H), 6.30(d, 2H), 6.37-6.40(d, 1H),7.02-7.06(m, 1H), 7.23-7.36(m, 10H); LRMS APCI m/z 459 [M+H]⁺.

EXAMPLE 85-[(3R)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

A solution of the product of preparation 15 (40 g, 93 mmol) intetrahydrofuran (1 L) was cooled to −30° C. Zirconium chloride (44 g,186 mmol) was added and the reaction mixture was stirred at −30° C. for1 hour. Methyl magnesium chloride (3M in tetrahydrofuran, 300 mL, 900mmol) was then added dropwise and the mixture was stirred for 2 hours,with the temperature maintained below −10° C. The reaction was quenchedwith 1M aqueous sodium hydroxide solution (300 mL) and the mixture wasthen decanted off. The residual solid was extracted with ethyl acetate(2×500 mL) and the combined organic solution was evaporated underreduced pressure. The residue was then dissolved in dichloromethane (1L), washed with water (200 mL) and concentrated in vacuo. The crudematerial was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 97.5:2.5, and the subsequent residueazeotroped with pentane (2×250 mL), diethyl ether (2×250 mL) and pentane(2×250 mL) to afford the title compound as a solid.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.04(s, 3H), 1.42-1.54(m, 2H),1.78-1.86(m, 1H), 1.93-2.02(m, 1H), 2.47-2.60(m, 3H), 2.63-2.77(m, 3H),4.04-4.08(m, 1H), 4.43-4.49(s, 2H), 7.23-7.43(m, 15H); LRMS APCI m/z 439[M+H]⁺

EXAMPLE 95-[(3R)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 8, using thesame method as that described for example 2, as a solid in 89% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99-1.01(m, 6H), 1.24-1.28(m, 2H),1.75-1.82(m, 1H), 1.88-1.97(m, 1H), 2.40-2.44(m, 2H), 2.49-2.68(m, 2H),2.71-2.76(m, 1H), 4.00-4.05(m, 1H), 4.39-4.46(m, 2H), 7.22-7.38(m, 15H);LRMS APCI m/z 425 [M+H]⁺

EXAMPLE 105-[(3S)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of preparation 14,using the same method as that described for example 1. The crudecompound was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 99:1:0.1 to 92:8:0.8, toafford the desired product as a brown oil in 76% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.04(s, 3H), 1.41-1.55(m, 2H),1.77-1.85(m, 1H), 1.93-2.01(m, 1H), 2.50-2.55(m, 3H), 2.63-2.77(m, 3H),4.03-4.08(m, 1H), 4.45(s, 2H), 7.22-7.42(m, 15H); LRMS APCI m/z 439[M+H]⁺

EXAMPLE 115-[(3S)-3-(Benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 10, usingthe same method as that described for example 2. The crude compound waspurified by column chromatography on silica gel, eluting with ethylacetate:methanol:0.88 ammonia, 98:2:0.2 to afford the desired product asa colourless gum in 78% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.00(s, 3H), 1.23-1.27(m, 2H),1.73-1.80(m, 1H), 1.87-1.96(m, 1H), 2.40-2.65(m, 5H), 2.69-2.73(m, 1H),3.98-4.03(m, 1H), 4.42(m, 2H), 7.22-7.32(m, 11H), 7.35-7.38(m, 4H); LRMSAPCI m/z 458 [M+H]⁺

EXAMPLE 125-[(3R)-3-(3-Methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

A solution of triphenyl phosphine (272 mg, 1.04 mmol) in tetrahydrofuran(3 mL) and di-isopropylazodicarboxylate (0.20 mL, 1.04 mmol) were addedto a solution of the product of preparation 16 (190 mg, 0.52 mmol) intetrahydrofuran (2 mL) and the mixture was stirred at room temperaturefor 15 minutes. A solution of 3-methoxyphenol (129 mg, 1.04 mmol) intetrahydrofuran (2 mL) was added and the mixture was stirred at roomtemperature for 2.5 hours. The reaction mixture was then concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol, 95:5 to 90:10, to afford thetitle compound as a colourless oil in 7% yield, 20 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.05(s, 3H), 1.10(s, 3H), 1.18-1.37(m, 2H),1.92-2.00(m, 1H), 2.10-2.16(m, 1H), 2.40-2.45(m, 2H), 2.72-2.95(m, 3H),2.97-3.05(m, 1H), 3.74(s, 3H), 4.80-4.14(m, 1H), 6.38-6.40(m, 2H),6.51(d, 1H), 7.12-7.16(m, 2H), 7.22-7.37(m, 9H); LRMS APCI m/z 472[M+H]⁺

EXAMPLE 135-[(3R)-3-(3-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 0.17 mL, 169 mmol) was added toa solution of the product of example 12 (20 mg, 42 mmol) indichloromethane (2 mL) and the mixture was stirred at room temperature.The reaction was monitored by tlc analysis and portions of borontribromide (1M in dichloromethane, 0.17 mL, 42 mmol) were added atregular intervals until all of the starting material had been consumed.After a period of 8 days, the reaction mixture was quenched with 0.88ammonia solution, stirred at room temperature for 1 hour then extractedwith dichloromethane (3×5 mL). The combined organic solution was driedover sodium sulfate, concentrated in vacuo and the residue was purifiedby column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 92:8:0.8. Theappropriate fractions were evaporated under reduced pressure and theresidue was dissolved in ethanol. Ammonium formate (12 mg, 0.19 mmol)and 20% Pd(OH)₂/C (2 mg) were added and the mixture was heated underreflux for 4 hours. The reaction mixture was then cooled to roomtemperature, filtered through Arbocel® and the filtrate was concentratedin vacuo. The filtrate was partitioned between ethyl acetate (8 mL) andaqueous ammonia solution (2 mL) and the aqueous layer was separated andextracted with further ethyl acetate (2×3 mL). The combined organicsolution was dried over sodium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 95:5:0.5, to afford thetitle compound as a colourless gum in 68% yield, 5.8 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.05(s, 3H), 1.23-1.28(m, 2H),1.85-1.90(m, 1H), 2.06-2.12(m, 1H), 2.40-2.45(m, 2H), 2.57-2.69(m, 2H),2.72-2.79(m, 1H), 2.85-2.90(m, 1H), 4.70-4.73(m, 1H), 6.26-6.30(m, 2H),6.36(d, 1H), 7.00-7.04(m, 1H), 7.21-7.25(m, 2H), 7.27-7.31(m, 4H),7.33-7.36(m, 4H); LRMS ESI m/z 459 [M+H]⁺

EXAMPLE 145-Methyl-5-[(3S)-3-(3-methylphenoxy)pyrrolidin-1-yl]-2,2-diphenylhexanamide

Di-isopropylazodicarboxylate (65 μL, 0.34 mmol) and the product ofpreparation 17 (62 mg, 0.17 mmol) were added to a solution of triphenylphosphine (89 mg, 0.34 mmol) in tetrahydrofuran (5 mL) and the mixturewas stirred at room temperature for 15 minutes. A solution of3-methylphenol (27 mg, 0.25 mmol) in tetrahydrofuran (1 mL) was addedand the mixture was stirred at room temperature for 2 hours. Thereaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 93:7, to afford the title compound asa colourless gum in 43% yield, 33 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.03(s, 3H), 1.21-1.26(m, 2H),1.82-1.90(m, 1H), 2.05-2.13(m, 1H), 2.27(s, 3H), 2.40-2.45(m, 2H),2.51-2.61(m, 2H), 2.68-2.74(m, 1H), 2.81-2.85(m, 1H), 4.71-4.75(m, 1H),6.57-6.62(m, 2H), 6.72(d, 1H), 7.08-7.12(m, 1H), 7.35-7.20(m, 10H); LRMSAPCI m/z 457 [M+H]⁺

EXAMPLE 155-[(3R)-3-(1,3-Benzoxazol-6-yloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Diethyl azodicarboxylate (125 μL, 0.74 mmol) and a solution of6-benzoxazol [(100 mg, 0.74 mmol), U.S. Pat. No. 613,027, p 56] intetrahydrofuran (2 mL) were added to an ice-cooled solution of triphenylphosphine (195 mg, 0.74 mmol) in tetrahydrofuran (2 mL) and the mixturewas stirred at 0° C. for 10 minutes and at room temperature for 90minutes. A solution of the product of preparation 16 (238 mg, 0.65 mmol)in tetrahydrofuran (2 mL) was then added and the mixture was stirred atroom temperature for 18 hours. The reaction mixture was then partitionedbetween ethyl acetate and dilute sodium carbonate solution and theaqueous layer was separated and extracted with ethyl acetate (×2). Thecombined organic solution was dried over magnesium sulfate, concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol, 90:10 to afford the titlecompound in 29% yield, 90 mg.

LRMS APCI m/z 484 [M+H]⁺

EXAMPLES 16 AND 17

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 15, usingthe product of preparation 17 and commercially available phenols. Thereactions were monitored by tlc analysis and were stirred at roomtemperature for 18-96 hours.

No. Data Yield 16 X = 4-Cl 35%5-[(3S)-3-(4-Chlorophenoxy)pyrrolidin-1-yl]-5-methyl-2.2-diphenylhexanamide ¹HNMR(400 MHz, CD₃OD) δ : 0.99(s, 3H), 1.05(s, 3H),1.23-1.27(m, 2H), 1.85-1.92(m, 1H), 2.07-2.16(m, 1H), 2.39-2.45(m, 2H),2.57- 2.67(m, 2H), 2.72-2.77(m, 1H), 2.85-2.89(m, 1H), 4.73-4.76(m, 1H),6.80(d, 2H), 7.19-7.36(m, 12H); LRMS APCI m/z 477 [M + H]⁺ 17 X = 3-Br38% 5-[(3s)-3-(3-Bromophenoxy)pyrrolidin-1-yl]-5-methyl-2.2-diphenylhexanamide ¹HNMR(400 MHz, CD₃OD) δ : 1.00(s, 3H), 1.05(s, 3H),1.22-1.26(m, 2H), 1.85-1.93(m, 1H), 2.08-2.17(m, 1H), 2.36-2.49(m, 2H),2.56- 2.66(m, 2H), 2.71-2.79(m, 1H), 2.83-2.91(m, 1H), 4.76-4.79(m, 1H),6.78-6.81(m, 1H), 6.99-7.35(m, 13H)

EXAMPLE 185-{(3S)-3-[(3′-Hydroxybiphenyl-4-yl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

Di-isopropylazodicarboxylate (0.21 mL, 1.09 mmol) and the product ofpreparation 17 (218 mg, 1.09 mmol) were added to a solution of triphenylphosphine (286 mg, 1.09 mmol) in tetrahydrofuran (5 mL) and the mixturewas stirred at room temperature for 15 minutes. A solution of3-methoxy-1,1′-biphenyl-4-ol [(200 mg, 0.55 mmol) Bioinorganic andMedicinal Chemistry, 2003, 11, 2347] in tetrahydrofuran (2 mL) was addedand the mixture was stirred at room temperature for 4 hours. Thereaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 93:7. The appropriate fractions wereevaporated under reduced pressure and the residue was further purifiedby column chromatography on silica gel, eluting with pentane:ethylacetate/methanol/0.88 ammonia (90:10:1), 100:0 to 50:50. The appropriatefractions were concentrated in vacuo and the residue was dissolved indichloromethane (2 mL). Boron tribromide (1M in dichloromethane, 0.58mL, 0.58 mmol) was added and the mixture as stirred at room temperaturefor 90 minutes. The reaction was then quenched by the dropwise additionof 0.88 ammonia solution and the mixture was stirred at room temperaturefor a further 30 minutes. The reaction mixture was then extracted withdichloromethane (3×20 mL) and the combined organic solution wasconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with pentane:ethylacetate/methanol/0.88 ammonia (90:10:1), 100:0 to 50:50, to afford thetitle compound as a foam in 5% yield, 14 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.96(s, 3H), 1.04(s, 3H), 1.21-1.26(m, 2H),1.86-1.93(m, 1H), 2.10-2.15(m, 1H), 2.39-2.46(m, 2H), 2.52-2.57(m, 1H),2.62(dd, 1H), 2.70-2.76(m, 1H), 2.83(dd, 1H), 4.73-4.79(m, 1H),6.70-6.72(dd, 1H), 6.84-6.87(m, 2H), 6.97-7.02(m, 2H), 7.18-7.57(m,13H); LRMS APCI m/z 535 [M+H]⁺

EXAMPLE 195-{(3S)-3-[(3′-Hydroxybiphenyl-3-yl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of preparation 17 and3-methoxy-1,1′-biphenyl-3-ol [WO 2003 006437, p 45], using the samemethod as that described for example 18, as a colourless gum in 16%yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.03(s, 3H), 1.21-1.25(m, 2H),1.87-1.94(m, 1H), 2.09-2.18(m, 1H), 2.40-2.45(m, 2H), 2.53-2.58(m, 1H),2.61-2.64(dd, 1H), 2.71-2.76(m, 1H), 2.82-2.87(dd, 1H), 4.80-4.83(m,1H), 6.76-6.76(m, 2H), 6.97-7.04(m, 3H), 7.12(d, 1H), 7.16-7.35(m, 12H);LRMS APCI m/z 535 [M+H]⁺

EXAMPLE 205-{(3S)-3-[(6-Hydroxy-2-naphthyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

Ammonium fluoride (27 mg, 0.738 mmol) was added to a solution of theproduct of preparation 19 (46 mg, 0.0738 mmol) in methanol (3 mL) andwater (0.3 mL) and the mixture stirred at room temperature for 18 hours.The mixture was concentrated in vacuo and the residue purified using aRediSep® silica gel cartridge eluting with dichloromethane:methanol:0.88ammonia (100:0:0 to 92:8:0.8). Appropriate fractions were concentratedin vacuo and the residue was dissolved in diethyl ether (30 ml), washedwith water (2×10 ml), dried over magnesium sulphate and concentrated invacuo to afford the title compound as an off-white foam in 35% yield, 14mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.06(s, 3H), 1.17-1.26(m, 2H),1.88-1.98(m, 1H), 2.09-2.25(m, 1H), 2.33-2.51(m, 2H), 2.54-2.62(m, 1H),2.63-2.68(m, 1H), 2.71-2.80(m, 1H), 2.81-2.91(m, 1H), 4.80-4.95(m, 1H),6.89-7.00(m, 2H), 7.00-7.06(m, 2H), 7.10-7.26(m, 6H), 7.26-7.35(m, 4H),7.47-7.54(m, 1H), 7.56-7.62(m, 1H); LRMS APCI m/z 509 [M+H]⁺

EXAMPLE 215-[(3S)-3-(2-Hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Di-isopropylazodicarboxylate (0.22 mL, 1.12 mmol) was added to anice-cooled solution of the product of preparation 17 (205 mg, 0.56mmol), triphenyl phosphine (293 mg, 1.12 mmol), and 2-hydroxyphenol (616mg, 5.59 mmol) in tetrahydrofuran (4 mL) the solution was stirred withice cooling for 2 hours. Triphenyl phosphine (293 mg, 1.12 mmol) anddi-isopropylazodicarboxylate (0.22 mL, 1.12 mmol) were added and theresulting solution was stirred at room temperature for 16 hours.Di-isopropylazodicarboxylate (0.22 mL, 1.12 mmol) was added and thesolution was stirred at room temperature for 4 hours. Tlc analysisindicated complete reaction. The reaction mixture was then concentratedin vacuo and the residue was purified using an Isolute® SCX-2 cartridge,eluting with methanol followed by 1M ammonia in methanol. The basicfractions were evaporated under reduced pressure and the residue waspurified by column chromatography on silica gel, eluting withpentane:(ethyl acetate:methanol:0.88 ammonia, 90:10:1) 1:0 to 1:1, toafford the title compound as a brown gum in 38% yield, 98 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.06(s, 3H), 1.25-1.29(m, 2H),1.87-1.94(m, 1H), 2.03-2.11(m, 1H), 2.41-2.45(m, 2H), 2.51-2.57(m, 1H),2.66-2.70(dd, 1H), 2.75-2.84(m, 2H), 4.80-4.85(m, 1H), 6.71-6.84(m, 4H),7.21-7.37(m, 10H); LRMS APCI m/z 459 [M+H]⁺458 [M−1]⁻

EXAMPLE 225-[(3S)-3-(4-methoxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Di-isopropylazodicarboxylate (0.21 mL, 1.09 mmol) was added to asolution of the product of preparation 17 (200 mg, 0.546 mmol),triphenyl phosphine (286 mg, 1.09 mmol), and 4-methoxyphenol (135 mg,1.09 mmol) in tetrahydrofuran (3 mL) the solution was stirred at roomtemperature for 16 hours. The reaction mixture was then concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with pentane:ethyl acetate, 100:0 to 50:50 The productcontaining fractions were evaporated under reduced pressure and theresidue was further purified by column chromatography on silica gel,eluting with ethyl acetate:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5 toafford the title compound as a white foam in 14% yield, 36 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.96(s, 3H), 1.02(s, 3H), 1.19-1.25(m, 2H),1.81-1.91(m, 1H), 2.00-2.11(m, 1H), 2.35-2.60(m, 4H), 2.66-2.72(m, 1H),2.77-2.81(m, 1H), 3.73(s, 3H), 4.64-4.69(m, 1H), 6.72-6.81(m, 4H),7.20-7.39(m, 10H); LRMS APCI m/z 473 [M+H]⁺

EXAMPLE 235-[(3S)-3-(4-hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 0.76 mL, 0.761 mmol) was addedto a solution of the product of example 22 (36 mg, 0.0761 mmol) indichloromethane (3 mL) and the mixture was stirred at room temperaturefor 1 hour. Tlc analysis indicated complete reaction. The reactionmixture was quenched via dropwise addition of 0.88 ammonia (2 mL) andstirred for 30 minutes to allow gas evolution. The reaction mixture waspartitioned and aqueous was extracted with dichloromethane (2×5 mL).Combined organic fractions were concentrated in vacuo and the residuewas purified by column chromatography on silica gel, eluting with ethylacetate to 95:5:0.5 ethyl acetate:methanol:0.88 ammonia to afford thetitle compound as a white foam in 46% yield, 16 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.03(s, 3H), 1.20-1.25(m, 2H),1.81-1.89(m, 1H), 2.01-2.09(m, 1H), 2.39-2.44(m, 2H), 2.51-2.61(m, 2H),2.67-2.73(m, 1H), 2.77-2.81(m, 1H), 4.62-4.66(m, 1H), 6.63-6.69(m, 4H),7.21-7.37(m, 10H); LRMS APCI m/z 458 [M−1]⁻

EXAMPLE 245-[(3S)-3-(4-trifluromethyl-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Di-isopropylazodicarboxylate (0.1 mL, 0.546 mmol) was added to asolution of the product of preparation 17 (100 mg, 0.273 mmol),triphenyl phosphine (143 mg, 0.546 mmol), and 4-trifluromethylphenol (88mg, 0.546 mmol) in tetrahydrofuran (3 mL) the solution was stirred atroom temperature for 4 hours. The reaction mixture was then concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with pentane:(ethyl acetate:methanol:0.88 ammonia,90:10:1), 1:0 to 1:1 to afford the title compound as a white foam in 34%yield, 48 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.03(s, 3H), 1.21-1.26(m, 2H),1.84-1.92(m, 1H), 2.11-2.20(m, 1H), 2.35-2.50(m, 2H), 2.52-2.62(m, 2H),2.69-2.75(m, 1H), 2.85-2.89(m, 1H), 4.81-4.86(m, 1H), 6.93-6.96(d, 2H),7.20-7.35(m, 10H), 7.52-7.54(d, 2H); LRMS APCI m/z 511 [M+H]⁺510 [M−1]⁻

EXAMPLE 255-[(3R)-3-(4-Trifluoromethyl-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.574 mmol) wasadded to an ice-cooled solution of the product of preparation 20 (100mg, 0.287 mmol) in N,N-dimethylformamide (1.5 mL) and the mixture wasstirred at 0° C. for 30 minutes. 4-fluorobenzotrifluoride (71 mg, 0.431mmol) in N,N-dimethylformamide (0.5 mL) was added and the mixture wasstirred for 16 hours, allowing the temperature to rise to 25° C. Thesolution was stirred at 50° C. for 24 hours and then stirred at 25° C.for 48 hours. Sodium hydride (60% dispersion in mineral oil, 23 mg,0.574 mmol) was added and the solution was stirred for 1.25 hours at 50°C. The reaction mixture was then cooled to 25° C. and quenched withwater (8 mL), concentrated in vacuo and the aqueous residue waspartitioned between ethyl acetate (10 mL) and water (10 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×15 mL). Thecombined organic solution was washed with brine (5 mL), concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with pentane:ethyl acetate, 3:1 to 0:1, to afford the titlecompound as a colourless gum in 70% yield, 10 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.07(s, 3H), 1.44-1.48(m, 2H),1.88-1.95(m, 1H), 2.16-2.25(m, 1H), 2.49-2.53(m, 2H), 2.56-2.62(m, 1H),2.67-2.70(m, 1H), 2.75-2.80(q, 1H), 2.89-2.93(dd, 1H), 4.85-4.89(m, 1H),6.96-6.98(d, 2H), 7.42-7.45(m, 10H), 7.53-7.55(d, 2H); LRMS APCI m/z 493[M+H]⁺

EXAMPLE 265-[(3R)-3-(4-trifluromethyl-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Potassium hydroxide (23 mg, 0.406 mmol) was added to a solution ofexample 25 (10 mg, 0.0203 mmol) in 3-methyl-3-pentanol (2 mL) and themixture was heated under reflux for 16 hours. The solution was cooled to25° C. and potassium hydroxide (23 mg, 0.406 mmol) was added and thesolution was heated under reflux for an additional 24 hours. Thereaction mixture was then cooled to room temperature, concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with ethyl acetate:methanol:0.88 ammonia, 95:5:0.5. toafford the title compound as a colourless gum in 68% yield, 7 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.03(s, 3H), 1.20-1.25(m, 2H),1.84-1.91(m, 1H), 2.10-2.20(m, 1H), 2.34-2.49(m, 2H), 2.52-2.61(m, 2H),2.69-2.74(m, 1H), 2.84-2.88(dd, 1H), 4.81-4.85(m, 1H), 6.94-6.96(d, 2H),7.20-7.35(m, 10H), 7.53-7.55(d, 2H); LRMS APCI m/z 511 [M+H]⁺510 [M−1]⁻

EXAMPLE 275-[(3R)-3-(3-chloro-4-methoxy-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

Sodium hydride (60% dispersion in mineral oil, 31 mg, 0.776 mmol) wasadded to an ice-cooled solution of the product of preparation 20 (135mg, 0.388 mmol) in N,N-dimethylformamide (4 mL) and the mixture wasstirred at 0° C. for 15 minutes. 2-chloro-4-fluoro-anisole (93 mg, 0.582mmol) in N,N-dimethylformamide (1 mL) was added and the mixture wasstirred for 16 hours, at 50° C. The solution was cooled to 25° C. andsodium hydride (60% dispersion in mineral oil, 62 mg, 1.55 mmol) wasadded and the solution was stirred for 16 hours at 80° C. The reactionmixture was then cooled to 25° C. and quenched with water (3 mL),concentrated in vacuo and the aqueous residue was partitioned betweenethyl acetate (20 mL) and water (5 mL). The aqueous layer was separatedand extracted with ethyl acetate (2×20 mL). The combined organicsolution was washed with brine (10 mL), concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith pentane:(ethyl acetate:methanol:0.88ammonia, 90:10:1), 3:1 to 1:1.The product containing fractions were evaporated under reduced pressureand the residue was further purified using an Isolute® SCX-2 cartridge,eluting with methanol followed by 1M ammonia in methanol. The basicfractions were evaporated to afford the title compound as a yellow gumin 32% yield, 61 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.08(s, 3H), 1.28-1.31(m, 2H),1.76-1.80(m, 1H), 1.86-1.93(m, 1H), 2.09-2.18(m, 1H), 2.49-2.63(m, 2H),2.67-2.70(m, 1H), 2.76-2.87(m, 2H), 3.80(s, 3H), 4.71-4.75(m, 1H),6.74-6.77(dd, 1H), 6.89-6.95(dd, 1H), 7.24-7.46(m, 10H), 8.45-8.59(m,1H); LRMS APCI m/z 489 [M+H]⁺

EXAMPLE 285-[(3R)-3-(3-chloro-4-methoxy-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Potassium hydroxide (140 mg, 2.49 mmol) was added to a solution of theproduct of example 27 (61 mg, 0.125 mmol) in 3-methyl-3-pentanol (5 mL)and the mixture was heated under reflux for 16 hours. The solution wascooled to room temperature, concentrated in vacuo and the residue waspartitioned between dichloromethane (10 mL) and water (5 mL), aqueouswas extracted with dichloromethane (3×10 mL). Combined organics wereconcentrated under reduced pressure and the residue purified by columnchromatography on silica gel, eluting with ethyl acetate:methanol:0.88ammonia, 90:10:1. The product containing fractions were evaporated underreduced pressure to afford the title compound as a colourless gum in 33%yield, 21 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.09(s, 3H), 1.26-1.30(m, 2H),1.88-1.96(m, 1H), 2.05-2.14(m, 1H), 2.35-2.49(m, 2H), 2.70-2.75(m, 2H),2.82-2.88(m, 1H), 2.91-2.96(m, 1H), 3.81(s, 3H), 4.72-4.76(m, 1H),6.73-6.76(dd, 1H), 6.88-6.89(d, 1H), 6.94-6.96(d, 1H), 7.24-7.36(m,10H); LRMS APCI m/z 507 [M+H]⁺505 [M−1]⁻

EXAMPLE 295-[(3S)-3-(3-Hydroxy-5-methyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

Diisopropyl azodicarboxylate (212 μL, 1.093 mmol) was added in threeportions to an ice-cooled solution of triphenyl phosphine (287 mg, 1.093mmol), 5-methylresorcinol (678 mg, 5.464 mmol) and product frompreparation 17 (200 mg, 0.546 mmol) in tetrahydrofuran (8 mL) and themixture was stirred at 0° C. to room temperature for 2 hours. Thereaction mixture was concentrated in vacuo and residue purified using anIsolute® SCX-2 cartridge, eluting with methanol followed by 1M ammoniain methanol. Basic fractions were concentrated in vacuo and the residuewas purified by column chromatography on silica gel, eluting with ethylacetate:methanol:0.88 ammonia, 98:2:0.2 to 94:6:0.6 to afford the titlecompound as a white foam in 27% yield, 70 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.06(s, 3H), 1.24-1.27(m, 2H),1.87-1.93(m, 1H), 2.05-2.13(m, 1H), 2.19(s, 3H), 2.39-2.45(m, 2H),2.61-2.69(m, 2H), 2.75-2.81(m, 1H), 2.85-2.90(m, 1H), 4.69-4.73(m, 1H),6.07(s, 1H), 6.13(s, 1H), 6.21(s, 1H), 7.21-7.35(m, 10H); LRMS ESI m/z473 [M+H]⁺

EXAMPLE 305-[(3S)-3-(3-Hydroxy-2-methyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 and2-methylresorcinol, using the same method as that described for example29, to afford an off-white foam in 68% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.23-1.28(m, 2H),1.86-1.93(m, 1H), 1.98(s, 3H), 2.02-2.11(m, 1H), 2.41-2.45(m, 2H),2.57-2.67(m, 2H), 2.71-2.78(m, 1H), 2.88-2.92(m, 1H), 4.69-4.72(m, 1H),6.26-6.28(d, 1H), 6.38-6.40(d, 1H), 6.87-6.91(t, 1H), 7.21-7.24(m, 2H),7.27-7.30(t, 4H), 7.34-7.36(m, 4H); LRMS ESI m/z 473 [M+H]⁺

EXAMPLE 315-[(3S)-3-(2,4-Dichloro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 and4,6-dichlororesorcinol using the same method as that described forexample 29, with the addition of further triphenyl phosphine (2 eq) anddiisopropyl azodicarboxylate (2 eq) after both 18 hrs and 24 hrs, andsubsequent stirring for an additional 24 hrs, to afford an off-whitefoam in 21% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.06(s, 3H), 1.24-1.28(m, 2H),1.89-1.96(m, 1H), 2.05-2.14(m, 1H), 2.38-2.49(m, 2H), 2.59-2.70(m, 2H),2.75-2.81(m, 1H), 2.89-2.93(m, 1H), 4.71-4.74(m, 1H), 6.48 (s, 1H),7.21-7.24(m, 3H), 7.26-7.31(t, 4H), 7.34-7.37(m, 4H); LRMS APCI m/z 527[M+H]⁺

EXAMPLE 325-[(3S)-3-(4,5-Dichloro-2-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 and4,5-dichlorocatechol, using the same method as that described forexample 29, with the addition of further triphenyl phosphine (2 eq) anddiisopropyl azodicarboxylate (2 eq) after both 18 hrs and 24 hrs, andsubsequent stirring for an additional 24 hrs, to afford an off-whitefoam in 18% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.09(s, 3H), 1.19-1.31(m, 2H),1.90-1.97(m, 1H), 2.05-2.14(m, 1H), 2.34-2.49(m, 2H), 2.61-2.67(m, 1H),2.69-2.73(m, 1H) 2.76-2.79(m, 1H), 2.86-2.92(m, 1H), 4.78-4.83(m, 1H),6.85 (s, 1H), 6.94(s, 1H), 7.21-7.40(m, 10H); LRMS ESI m/z 527 [M+H]⁺

EXAMPLE 335-[(3S)-3-(3-Chloro-5-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

Diisopropyl azodicarboxylate (160 μL, 0.820 mmol) was added in threeportions to an ice-cooled solution of triphenyl phosphine (215 mg, 0.820mmol), 3-chloro-5-methoxyphenol (325 mg, 2.049 mmol) and the productfrom preparation 17 (150 mg, 0.410 mmol) in tetrahydrofuran (8 mL) andthe mixture was stirred at 0° C. to room temperature for 18 hours. Thereaction mixture was concentrated in vacuo and purified using anIsolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia inmethanol. Basic fractions were concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88ammonia, 98:2:0.2 to 94:6:0.6 to afford thetitle compound as a green gum in 97% yield, 200 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 3H), 1.03(s, 3H), 1.20-1.25(m, 2H),1.81-1.89(m, 1H), 2.06-2.14(m, 1H), 2.35-2.49(m, 2H), 2.51-2.60(m, 2H),2.67-2.73(m, 1H), 2.79-2.83(m, 1H), 3.75(s, 3H), 4.70-4.74(m, 1H),6.29-6.30(t, 1H), 6.41-6.42(t, 1H), 6.51-6.52(t, 1H), 7.20-7.24(m, 2H),7.26-7.30(t, 4H), 7.33-7.35(m, 4H); LRMS ESI m/z 507 [M+H]⁺

EXAMPLE 345-[(3S)-3-(3-Chloro-5-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

Boron tribromide (1M in dichloromethane, 1.97 mL, 1.976 mmol) was addedto an ice-cooled solution of the product of example 33 (200 mg, 0.395mmol) in dichloromethane (10 mL) and the mixture was stirred at 0° C. toroom temperature for 18 hours. The reaction was quenched with 0.88ammonia solution and stirred at room temperature for 90 minutes. Thereaction mixture was extracted with dichloromethane (3×10 mL) and thecombined organic solution was dried over sodium sulfate and concentratedin vacuo. Purification of the residue by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5,afforded the title compound as a white foam in 45% yield, 88 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.01(s, 3H), 1.06(s, 3H), 1.24-1.28(m, 2H),1.85-1.93(m, 1H), 2.06-2.15(m, 1H), 2.38-2.46(m, 2H), 2.61-2.69(m, 2H),2.74-2.81(m, 1H), 2.87-2.92(m, 1H), 4.70-4.74(m, 1H), 6.18-6.19(t, 1H),6.30-6.31(t, 1H), 6.38-6.39(t, 1H), 7.22-7.26(m, 2H), 7.28-7.31 (t, 4H),7.33-7.36(m, 4H); LRMS ESI m/z 493 [M+H]⁺

EXAMPLE 355-[(3S)-3-(4-Chloro-2-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 and4-chloro-2-methoxyphenol, using the same method as that described forexample 33, with stirring for 2 hrs and Isolute® SCX cartridgepurification to afford a colourless gum in 100% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.96(s, 3H), 1.02(s, 3H), 1.21-1.25(m, 2H),1.83-1.90(m, 1H), 2.02-2.11(m, 1H), 2.42-2.46(m, 2H), 2.48-2.54(m, 1H),2.62-2.66(dd, 1H), 2.69-2.80(m, 2H), 3.73(s, 3H), 4.68-4.73(m, 1H),6.75-6.77(d, 1H), 6.82-6.85(dd, 1H), 6.91-6.92(d, 1H), 7.20-7.23(m, 2H),7.26-7.29(t, 4H), 7.33-7.37(m, 4H); LRMS ESI m/z 473 [M+H]⁺

EXAMPLE 365-[(3S)-3-(4-Chloro-2-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 35, usingthe same method as that described for example 34, with stirring for 3hours and purification by column chromatography on silica gel, elutingwith ethyl acetate:methanol:ammonia, 98:2:0.2 to 94:6:0.6 to afford awhite foam in 72% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.96(s, 3H), 1.02(s, 3H), 1.21-1.25(m,2H),1.83-1.90(m, 1H), 2.02-2.11(m, 1H), 2.42-2.46(m, 2H), 2.48-2.54(m, 1H),2.62-2.66(dd, 1H), 2.69-2.80(m, 2H), 4.68-4.73(m, 1H), 6.75-6.77(d, 1H),6.82-6.85(dd, 1H), 6.91-6.92(d, 1H), 7.20-7.23(m, 2H), 7.26-7.29(t, 4H),7.33-7.37(m, 4H); LRMS ESI m/z 473 [M+H]⁺

EXAMPLE 375-[(3S)-3-(2-Chloro-3-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 andthe product of preparation 21, using the same method as that describedfor example 33, with Isolute® SCX cartridge purification to afford awhite foam in 100% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.23-1.28(m, 2H),1.88-1.95(m, 1H), 2.04-2.13(m, 1H), 2.42-2.46(m, 2H), 2.56-2.63(m, 1H),2.65-2.70(m, 1H), 2.72-2.79(m, 1H), 2.88-2.93(m, 1H), 3.85(s, 3H),4.79-4.81(m, 1H), 6.54-6.57(dd, 1H), 6.67-6.69(dd, 1H), 7.14-7.18(t, 1H)7.20-7.24(m, 2H), 7.27-7.30(t, 4H), 7.33-7.37(m, 4H); LRMS ESI m/z507[M+H]⁺

EXAMPLE 385-[(3S)-3-(2-Chloro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 37, usingthe same method as that described for example 34, to afford a white foamin 37% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.08(s, 3H), 1.12(s, 3H), 1.31-1.36(m, 2H),1.97-2.05(m, 1H), 2.07-2.16(m, 1H), 2.44-2.48(m, 2H), 2.77-2.96(m, 3H),3.05-3.10(q, 1H), 4.82-4.87(m, 1H), 6.43-6.45(dd, 1H), 6.54-6.57(dd,1H), 7.01-7.05(t, 1H), 7.22-7.26(m, 2H), 7.29-7.33(t, 4H), 7.36-7.39(m,4H); LRMS ESI m/z 493 [M+H]⁺

EXAMPLE 39 & 40

The following compounds were prepared from the product of preparation 17and 2-chlororesorcinol, using the same method as that described forexample 33, with the addition of further triphenyl phosphine (2 eq) anddiisopropyl azodicarboxylate (2 eq) after 18 hrs, and subsequentstirring for an additional 3 hrs. Crude material was purified by columnchromatography on silica gel, eluting with ethylacetate:methanol:0.88ammonia, 98:2:0.2 to 94:6:0.6, to yield a mixtureof regioisomers that were separated by HPLC on a Luna C8(2) acidiccolumn, eluting with acetonitrile:water:diethylamine, 1:1:0.05 to affordthe title compounds as white solids in 12% and 1% yield respectively.

EXAMPLE 395-[(3S)-3-(4-Chloro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.04(s, 3H), 1.23-1.27(q, 2H),1.87-1.95(m, 1H), 2.05-2.13(m, 1H), 2.41-2.47(m, 2H), 2.54-2.60(m, 1H),2.62-2.66(dd, 1H), 2.71-2.77(q, 1H), 2.86-2.90(q, 1H), 4.69-4.74(m, 1H),2-636(m, 2H), 7.07-7.09(d, 1H), 7.20-7.24(m, 2H), 7.27-7.30(t, 4H),7.35-7.37(m, 4H); LRMS ESI m/z 493 [M+H]⁺

EXAMPLE 405-[(3S)-3-(2-Chloro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.21-1.26(m, 2H),1.82-1.90(m, 1H), 2.05-2.15(m, 1H), 2.35-2.46(m, 2H), 2.53-2.62(m, 2H),2.69-2.75(q, 1H), 2.81-2.86(q, 1H), 4.66-4.71(m, 1H), 6.27-6.30(dd, 1H),6.39-6.40(d, 1H), 7.09-7.11(d, 1H), 7.21-7.36(m, 10H); LRMS ESI m/z 493[M+H]⁺

EXAMPLE 415-[(3R)-3-(3-Chloro-2-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The product of preparation 20 (150 mg, 0.431 mmol) in dimethylformamide(3 ml) was added drop wise to an ice-cooled solution of sodium hydride(60% dispersion in mineral oil, 52 mg, 1.293 mmol) in dimethylformamide(1 ml). After stirring for 1 hour the product of preparation 22 (103 mg,0.646 mmol) in dimethylformamide (1 ml) was added and the mixture washeated to 60° C. for 96 hours. The solution was concentrated in vacuoand partitioned between ethyl acetate (10 ml) and water (10 ml). Theorganic layer was extracted and washed again with water (10 ml), thendried over sodium sulphate and concentrated in vacuo, to afford thetitle compound as a brown oil in 74% yield, 156 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.08(s, 3H), 1.44-1.49(m, 2H),1.90-1.97(m, 1H), 2.12-2.21(m, 1H), 2.50-2.62(m, 3H), 2.74-2.83(m, 2H),2.87-2.91(m, 1H), 3.74(s, 3H), 4.81-4.84(m, 1H), 6.83-6.85(dd, 1H),6.93-7.00(m, 2H), 7.25-7.42(m, 10H); LRMS ESI m/z 489 [M+H]⁺

EXAMPLE 425-[(3R)-3-(3-Chloro-2-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 41, usingthe same method as that described for example 2. The crude compound waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5, to afford a white foam,in 50% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.05(s, 3H), 1.23-1.27(q, 2H),1.88-1.96(m, 1H), 2.07-2.16(m, 1H), 2.41-2.46(m, 2H), 2.56-2.61(m, 1H),2.64-2.77(m, 2H), 2.86-2.92(m, 1H), 3.75(s, 3H), 4.77-4.82(m, 1H),6.80-6.83(dd, 1H), 6.96-6.99(m, 2H), 7.21-7.25(m, 2H), 7.27-7.31(t, 4H),7.34-7.36(m, 4H); LRMS ESI m/z 507 [M+H]⁺

EXAMPLE 435-[(3R)-3-(3-Chloro-2-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 42, usingthe same method as that described for example 34, to afford a white foamin 65% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.05(s, 3H), 1.09(s, 3H), 1.28-1.32(m, 2H),1.89-1.98(m, 1H), 2.03-2.13(m, 1H), 2.42-2.46(m, 2H), 2.59-2.67(m, 1H),2.70-2.75(m, 1H), 2.81-2.93(m, 2H), 4.84-4.88(m, 1H), 6.66-6.70(t, 1H),6.77-6.79(d, 1H), 6.88-6.91 (d, 1H), 7.21-7.25(m, 2H), 7.28-7.32(t, 4H),7.35-7.37(m, 4H); LRMS ESI m/z 493 [M+H]⁺

EXAMPLE 445-[(3S)-3-(3-Hydroxy-2,5-dimethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 and2,5-dimethylresorcinol, using the same method as that described forexample 29, with the addition of further triphenyl phosphine (2 eq) anddiisopropyl azodicarboxylate (2 eq) after 18 hrs, and subsequentstirring for 1 hour to afford a pale brown foam in 58% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.24-1.28(m, 2H),1.85-1.92(m, 1H), 1.93(s, 3H), 2.01-2.10(m, 1H), 2.20(s, 3H),2.41-2.45(m, 2H), 2.56-2.66(m, 2H), 2.70-2.78(m, 1H), 2.86-2.93(m, 1H),4.67-4.873(m, 1H), 6.11(s, 1H), 6.24(s, 1H), 7.20-7.24(m, 2H),7.26-7.30(t, 4H), 7.33-7.37(m, 4H); LRMS APCI m/z 487 [M+H]⁺

EXAMPLE 455-[(3S)-3-(3-Fluoro-5-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 andthe product of preparation 23, using the same method as that describedfor example 33, to afford the product as a colourless gum in 100% yield.

LRMS ESI m/z 491[M+H]⁺

EXAMPLE 465-[(3S)-3-(3-Fluoro-5-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 45, usingthe same method as that described for example 34, with the addition offurther boron tribromide (1M in dichloromethane, 4 eq) after 3 hours,and subsequent stirring for 2 hrs. Crude material was purified by columnchromatography on silica gel, eluting with ethyl acetate:methanol:0.88ammonia, 98:2:0.2 to 94:6:0.6 to afford a white foam in 35% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.21-1.26(m, 2H),1.82-1.90(m, 1H), 2.05-2.14(m, 1H), 2.39-2.45(m, 2H), 2.54-2.63(m, 2H),2.69-2.75(m, 1H), 2.82-2.87(q, 1H), 4.66-4.71(m, 1H), 6.02-6.11(m, 3H),7.21-7.26(m, 2H), 7.27-7.31(t, 4H), 7.33-7.36(m, 4H); LRMS APCI m/z 477[M+H]⁺

EXAMPLE 475-[(3R)-3-(3-Methoxy-5-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from the product of preparation 20 andthe product of preparation 24, using the same method as that describedfor example 41. The residue was purified by column chromatography onsilica gel, eluting with dichloromethane:methanol:0.88 ammonia,95:5:0.5, to afford a pale brown gum in 32% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.08(s, 3H), 1.44-1.48(m, 2H),1.87-1.90(m, 1H), 2.14-2.22(m, 1H), 2.49-2.54(m, 2H), 2.56-2.62(m, 1H),2.67-2.70(d, 1H), 2.75-2.81(q, 1H), 2.87-2.91(m, 1H), 3.80(s, 3H),4.82-4.85(m, 1H), 6.61(s, 1H), 6.67(s, 1H), 6.74 (s, 1H), 7.24-7.42(m,10H); LRMS APCI m/z 523 [M+H]⁺

EXAMPLE 485-[(3R)-3-(3-Methoxy-5-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 47, usingthe same method as that described for example 2, to afford product acolourless gum in 83% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.02(s, 3H), 1.20-1.25(m, 2H),1.82-1.89(m, 1H), 2.08-2.17(m, 1H), 2.39-2.46(m, 2H), 2.49-2.59(m, 2H),2.66-2.72(q, 1H), 2.81-2.86(m, 1H), 3.80(s, 3H), 4.76-4.81(m, 1H),6.58-6.60(q, 1H), 6.64(s, 1H), 6.74(s, 1H), 7.18-7.36(m, 10H); LRMS APCIm/z 541 [M+H]⁺

EXAMPLE 495-[(3R)-3-(3-Hydroxy-5-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 48, usingthe same method as that described for example 34, to afford a colourlessgum in 40% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.22-1.27(m, 2H),1.84-1.91(m, 1H), 2.08-2.16(m, 1H), 2.38-2.47(m, 2H), 2.54-2.63(m, 2H),2.69-2.75(q, 1H), 2.85-2.89(m, 1H), 4.73-4.78(m, 1H), 6.45-6.47(t, 1H),6.52-6.53(s, 1H), 6.60-6.61(s, 1H), 7.21-7.24(m, 2H), 7.27-7.30(t, 4H),7.34-7.36(m, 4H); LRMS APCI m/z 527 [M+H]⁺

EXAMPLE 505-[(3S)-3-(4-Fluoro-3-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 andthe product of preparation 25, using the same method as that describedfor example 33, with the addition of further triphenyl phosphine (2 eq)and diisopropyl azodicarboxylate (2 eq) after both 16 hrs and 17 hrs,with subsequent stirring for an additional 1 hr and Isolute® SCXcartridge purification to afford a pale brown foam in 86% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.03(s, 3H), 1.21-1.26(m, 2H),1.82-1.89(m, 1H), 2.04-2.13(m, 1H), 2.37-2.47(m, 2H), 2.52-2.62(m, 2H),2.68-2.74(q, 1H), 2.81-2.85(m, 1H), 3.79(s, 3H), 4.69-4.73(m, 1H),6.28-6.32(m, 1H), 6.52-6.56(dd, 1H), 6.90-6.95(dd, 1H), 7.20-7.24(m,2H), 7.26-7.30(t, 4H), 7.33-7.36(m, 4H); LRMS APCI m/z 491 [M+H]⁺

EXAMPLE 515-[(3S)-3-(2-Fluoro-3-Methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 17 andthe product of preparation 26, using the same method as that describedfor example 33, with the addition of further triphenyl phosphine (2 eq)and diisopropyl azodicarboxylate (2 eq) after both 16 hrs and 17 hrs,with subsequent stirring for an additional 1 hr and Isolute® SCXcartridge purification to afford a pale yellow foam in 86% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.02(s, 3H), 1.22-1.26(m, 2H),1.85-1.93(m, 1H), 2.04-2.12(m, 1H), 2.40-2.45(m, 2H), 2.51-2.56(m, 1H),2.62-2.65(m, 1H), 2.68-2.74(q, 1H), 2.82-2.86(m, 1H), 3.83(s, 3H),4.74-4.78(m, 1H), 6.53-6.57(t, 1H), 6.66-6.70(t, 1H), 6.93-6.98(td, 1H),7.20-7.24(m, 2H), 7.27-7.30(t, 4H), 7.33-7.36(m, 4H); LRMS APCI m/z 491[M+H]⁺

EXAMPLE 525-[(3S)-3-(4-Fluoro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 50, usingthe same method as that described for example 34, with stirring for 3hours and purification by column chromatography on silica gel, elutingwith ethyl acetate:methanol:0.88 ammonia, 98:2:0.2 to 94:6:0.6. toafford a white foam in 52% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.22-1.27(m, 2H),1.82-1.90(m, 1H), 2.03-2.12(m, 1H), 2.38-2.46(m, 2H), 2.55-2.64(m, 2H),2.70-2.76(q, 1H), 2.83-2.87(m, 1H), 4.6-4.69(m, 1H), 6.19-6.23(dt, 1H),6.38-6.40(dd, 1H), 6.85-6.90(dd, 1H), 7.21-7.25(m, 2H), 7.27-7.31 (t,4H), 7.33-7.36(m, 4H); LRMS APCI m/z 477 [M+H]⁺

EXAMPLE 535-[(3S)-3-(2-Fluoro-3-Hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 51, usingthe same method as that described for example 34, with stirring for 3hours and purification by column chromatography on silica gel, elutingwith ethyl acetate:methanol:ammonia, 98:2:0.2 to 94:6:0.6 to afford awhite foam in 26% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.00 (s, 3H), 1.04(s, 3H), 1.24-1.28(m, 2H),1.88-1.95(m, 1H), 2.04-2.13(m, 1H), 2.41-2.47(m, 2H), 2.55-2.63(m, 1H),2.66-2.71(m, 1H), 2.72-2.78(q, 1H), 2.86-2.91(m, 1H), 4.73-4.77(m, 1H),6.38-6.42(t, 1H), 6.48-6.53(t, 1H), 6.80-6.85(td, 1H), 7.21-7.25(m, 2H),7.27-7.31(t, 4H), 7.34-7.37(m, 4H); LRMS ESI m/z 477 [M+H]⁺

EXAMPLE 545-[(3R)-3-(3-Hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

4M Hydrochloric acid in dioxane (3 ml) and water (0.3 ml) were added tothe product of preparation 29 (95 mg, 0.186 mmol) and the resultingsolution was stirred at 60° C. for 20 minutes. The reaction was cooledto room temperature and partitioned between ethyl acetate (20 ml) andsaturated sodium hydrogen carbonate solution (10 ml). The aqueous layerwas extracted and washed with ethyl acetate (2×10 ml) and the combinedorganic layers dried over sodium sulphate and concentrated in vacuo. Theresidue was purified by column chromatography, eluting with ethylacetate:methanol:0.88 ammonia, 97:3:0.2 to 95:5:0.5, to afford the titlecompound as a colourless gum in 51% yield, 44 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.00(s, 3H), 1.24-1.28(m, 2H),1.74-1.81(m, 1H), 1.87-1.94(m, 1H), 2.40-2.44(m, 2H), 2.49-2.58(m, 2H),2.61-2.67(m, 1H), 2.71-2.76(m, 1H), 3.98-4.03(m, 1H), 4.36(s, 2H),6.67-6.69(d, 1H), 6.74-6.76(m, 2H), 7.09-7.13(t, 1H), 7.22-7.26(m, 2H),7.29-7.32(t, 4H), 7.35-7.38(m, 4H); LRMS ESI m/z 473 [M+H]⁺

EXAMPLE 555-{(3S)-3-[(3-Bromobenzyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

Sodium hydride (60% dispersion in mineral oil, 150 mg, 3.74 mmol) wasadded portionwise to an ice-cooled solution of the product ofpreparation 18 (1.3 g, 3.74 mmol) in N,N-dimethylformamide (20 mL) andthe mixture was stirred at 0° C. for 1 hour. 3-Bromobenzylbromide (935mg, 3.74 mmol) was added and the mixture was stirred for 4 hours,allowing the temperature to rise to 25° C. The reaction mixture was thenquenched with water, concentrated in vacuo and the aqueous residue waspartitioned between ethyl acetate (50 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (4×30 mL). Thecombined organic solution was dried over sodium sulfate, concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with pentane:ethyl acetate, 50:50 to 100:0, to afford thetitle compound as a pale brown oil in 70% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.04(s, 3H), 1.41-1.54(m, 2H),1.77-1.85(m, 1H), 1.93-2.02(m, 1H), 2.49-2.54(m, 3H), 2.62-2.76(m, 3H),4.02-4.07(m, 1H), 4.43(m, 2H), 7.18-7.50(m, 14H); LRMS APCI m/z 518[M+H]⁺

EXAMPLE 565-{(3S)-3-[(3′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (16 mg, 19μmol) was added to a solution of the product of example 55 (205 mg, 0.38mmol), 3-hydroxyphenylboronic acid (106 mg, 0.77 mmol) and sodiumcarbonate (81 mg, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL)and the mixture was heated under reflux for 16 hours. The cooledreaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting with ethylacetate:methanol, 98:2 to 96:4, to afford the title compound in 25%yield, 51 mg.

¹HNMR(CD₃OD, 400 MHz) δ: 1.04(s, 3H), 1.06(s, 3H), 1.46-1.52(m, 2H),1.82-1.90(m, 1H), 1.96-2.03(m, 1H), 2.50-2.55(m, 3H), 2.67-2.80(m, 3H),4.08-4.13(m, 1H), 4.52(s, 2H), 6.76(dd, 1H), 7.01(m, 1H), 7.05(d, 1H),7.20-7.24(m, 1H), 7.27-7.42(m, 12H), 7.48(d, 1H), 7.54(s, 1H); LRMS ESIm/z 529[M−H]hu −

EXAMPLE 575-[(3S)-3-(Biphenyl-3-ylmethoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of example 55 andbenzeneboronic acid, using the same method as that described for example56, as a green gum in 54% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.11(s, 3H), 1.13(s, 3H), 1.51-1.58(m, 2H),1.94-2.03(m, 2H), 2.52-2.56(m, 2H), 2.70-2.77(m, 1H), 2.82-2.93(m, 3H),4.08-4.13 & 4.13-4.18(2×m, 1H), 4.45 & 4.54 (2×m, 2H), 7.26-7.43(m,19H); LRMS APCI m/z 516 [M+H]⁺

EXAMPLE 585-{(3S)-3-[(2′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of example 55 and2-hydroxyphenylboronic acid, using the same method as that described forexample 56. The crude compound was purified by column chromatography onsilica gel, eluting with ethyl acetate followed bydichloromethane:methanol, 95:5, to afford the desired product as palebrown foam in 61% yield.

¹HNMR(CD₃OD, 400 MHz) δ: 1.03(s, 3H), 1.07(s, 3H), 1.47-1.53(m, 2H),1.83-1.90(m, 1H), 1.94-2.03(m, 1H), 2.50-2.55(m, 2H), 2.57-2.64(m, 1H),2.69-2.83(m, 3H), 4.09-4.14(m, 1H), 4.51(s, 2H), 6.85-6.89(m, 2H),7.14(m, 1H), 7.20-7.46(m, 14H), 7.51(s, 1H); LRMS ESI m/z 529[M−H]⁻

EXAMPLE 595-{(3S)-3-[(4-Bromobenzyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

Sodium hydride (60% dispersion in mineral oil, 35 mg, 0.88 mmol) wasadded portionwise to an ice-cooled solution of the product ofpreparation 18 (205 mg, 0.59 mmol) in N,N-dimethylformamide (5 mL) andthe mixture was stirred for 1 hour. 4-Bromobenzylbromide (220 mg, 0.88mmol) was added and the mixture was stirred for 3 hours, allowing thetemperature to rise to 25° C. The reaction mixture was then re-cooled to0° C., further sodium hydride (60% dispersion in mineral oil, 220 mg,0.88 mmol) was added and the mixture was stirred at room temperature.After 18 hours, the mixture was re-cooled to 0° C. and sodium hydride(60% dispersion in mineral oil, 293 mg, 1.17 mmol) was added. Afterstirring for 1 hour, further 4-bromobenzylbromide (220 mg, 0.88 mmol)was added and the mixture was stirred for 3 hours at room temperature.The reaction mixture was then quenched with water, concentrated in vacuoand the aqueous residue was partitioned between ethyl acetate (50 mL)and water (30 mL). The organic layer was separated, dried over sodiumsulfate, concentrated in vacuo and the residue purified using anIsolute® SCX-2 cartridge, eluting with methanol followed by 0.5M ammoniain methanol. The basic fractions were evaporated under reduced pressureand the residue further purified by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 95:5:5 to afford thetitle compound as a pale orange gum.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 3H), 1.05(s, 3H), 1.40-1.53(m, 2H),1.77-1.85(m, 1H), 1.93-2.02(m, 1H), 2.50-2.55(m, 3H), 2.64-2.78(m, 3H),4.03-4.08(m, 1H), 4.42(s, 2H), 7.23(d, 2H), 7.28-7.44(m, 12H); LRMS APCIm/z 519 [M+H]⁺

EXAMPLE 605-{(3S)-3-[(3′-Hydroxybiphenyl-4-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (12 mg, 14μmol) was added to a solution of the product of example 59 (150 mg, 0.29mmol), 3-hydroxyphenylboronic acid (80 mg, 0.58 mmol) and sodiumcarbonate (62 mg, 0.58 mmol) in tetrahydrofuran (5.5 mL) and water (1mL) and the mixture was heated under reflux for 18 hours. Further1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (12 mg, 14μmol) was added and the mixture was heated under reflux for 6 hoursbefore cooling to room temperature. The reaction mixture was thenconcentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 100:0:0 to 95:5:0.5, to afford the title compound as a palebrown foam in 47% yield, 73 mg.

LRMS ESI m/z 531 [M+H]⁺

EXAMPLE 615-{(3S)-3-[(3′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 56, usingthe same method as that described for example 2, as a colourless gum in17% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.22(s, 3H), 1.24(s, 3H), 1.42-1.47(m, 2H),1.96-2.06(m, 1H), 2.11-2.19(m, 1H), 2.42-2.47(m, 2H), 3.14-3.23(m, 4H),4.23-4.27(m, 1H), 4.56(m, 2H), 6.76-6.79(dd, 1H), 7.02(m, 1H), 7.06(d,1H), 7.23-7.41(m, 13H), 7.49-7.51(d, 1H), 7.54(s, 1H); LRMS ESI m/z 549[M+H]⁺

EXAMPLE 625-{(3S)-3-[(4′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of example 55 and4-hydroxyphenylboronic acid, using the same method as that described forexample 56. The crude compound was purified by column chromatography onsilica gel, eluting with ethyl acetate. The appropriate fractions wereevaporated under reduced pressure and the residue was further purifiedby column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 98:2:0.2 to 95:5:0.5, to affordthe desired compound as a pale brown gum in 78% yield.

¹HNMR(CD₃OD, 400 MHz) δ: 1.03(s, 3H), 1.06(s, 3H), 1.46-1.52(m, 2H),1.80-1.88(m, 1H), 1.93-2.02(m, 1H), 2.49-2.60(m, 3H), 2.66-2.80(m, 3H),4.04-4.09(m, 1H), 4.44(s, 2H), 6.80(d, 2H), 7.26-7.43(m, 15H), 7.50(s,1H); LRMS ESI m/z 529[M−H]⁻

EXAMPLE 635-{(3S)-3-[(4′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 62, usingthe same method as that described for example 2, in 6% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.02(s, 3H), 1.25-1.29(m, 2H),1.78-1.87(m, 1H), 1.88-1.99(m, 1H), 2.40-2.44(m, 2H), 2.52-2.59(m, 1H),2.60-2.71(m, 2H), 2.72-2.78(m, 1H), 4.03-4.08(m, 1H), 4.48(s, 2H),6.84(d, 2H), 7.20-7.38(m, 12H), 7.41-7.45(m, 3H), 7.48(s, 1H); LRMS ESIm/z 549 [M+H]⁺

EXAMPLE 645-{(3S)-3-[(2′-Hydroxybiphenyl-3-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 58, usingthe same method as that described for example 2. The crude was purifiedby column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 90:10:1 to 80:20:2, to afford thedesired product as a white solid in 21% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.00(s, 3H), 1.23-1.27(m, 2H),1.75-1.84(m, 1H), 1.88-1.98(m, 1H), 2.39-2.44(m, 2H), 2.47-2.66(m, 3H),2.71-2.75(m, 1H), 4.02-4.08(m, 1H), 4.47(s, 2H), 6.86-6.89(m, 2H),7.12-7.16(m, 1H), 7.20-7.37(m, 13H), 7.44(d, 1H), 7.49(s, 1H); LRMS ESIm/z 549 [M+H]⁺

EXAMPLE 655-{(3S)-3-[(3′-Hydroxybiphenyl-4-yl)methoxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 60, usingthe same method as that described for example 2. The crude was purifiedby column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 90:10:1, to affordthe desired product as a white solid in 28% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.05(s, 3H), 1.27-1.31(m, 1H),1.52-1.56(m, 1H), 1.81-1.89(m, 1H), 1.90-2.00(m, 1H), 2.34-2.38(m, 1H),2.41-2.45(m, 2H), 2.59-2.64(m, 1H), 2.67-2.76(m, 1H), 2.79-2.83(m, 1H),4.04-4.10(m, 1H), 4.47(m, 2H), 6.75(d, 1H), 7.01 (m, 1H), 7.05(d, 1H),7.18-7.38(m, 11H), 7.43(d, 2H), 7.53(d, 2H); LRMS ESI m/z 549 [M+H]⁺

EXAMPLE 665-[(3S)-3-(Biphenyl-3-ylmethoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 57, usingthe same method as that described for example 2, as a brown gum in 23%yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.18(s, 3H), 1.20(s, 3H), 1.38-1.44(m, 2H),1.97-2.04(m, 1H), 2.05-2.12(m, 1H), 2.41-2.46(m, 2H), 3.03-3.14(m, 4H),4.21-4.24(m, 1H), 4.56(m, 2H), 7.23-7.44(m, 16H), 7.50-7.55(m, 1H),7.57-7.60(m, 2H); LRMS APCI m/z 533 [M+H]⁺

EXAMPLE 675-[(3R)-3-(4-Fluoro-3-hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Hydrochloric acid in dioxane (4M, 4 ml) and water (0.5 ml) were added tothe product of preparation 34 (150 mg, 0.248 mmol) and the resultingsolution refluxed for 45 minutes. The solvent was removed in vacuo andthe residue partitioned between ethyl acetate (10 ml) and saturatedsodium hydrogen carbonate solution (3 ml). The aqueous layer wasseparated and extracted with further ethyl acetate (2×10 ml). Thecombined organic layers were washed with water (5 ml), brine (5 ml),dried over sodium sulphate and concentrated in vacuo. The residue waspurified by column chromatography, eluting withdichloromethane:methanol:0.88 ammonia (95:5:0.5 to 93:7:0.7 to 90:10:1)to afford the title compound as an off-white foam in 44% yield, 54 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.05(s, 3H), 1.06(s, 3H), 1.28-1.33(m, 2H),1.81-1.97(m, 2H), 2.41-2.45(m, 2H), 2.63-2.86(m, 4H), 4.02-4.07(m, 1H),4.34(s, 2H), 6.70-6.74(m, 1H), 6.87-6.90(dd, 1H), 6.94-6.99(dd, 1H),7.23-7.38(m, 10H); LRMS ESI m/z 491 [M+H]⁺

EXAMPLE 685-[(3S)-3-(3-Cyano-5-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Ammonium formate (33 mg, 0.523 mmol) and 20% Pd(OH)₂C (3 mg) were addedto a solution of the product of preparation 36 (30 mg, 0.0523 mmol) inethanol (2 mL) and the mixture refluxed for 15 minutes. The reactionmixture was then filtered through Arbocel® and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with dichloromethane:methanol:0.88ammonia(95:5:0.5) to afford the title compound as a yellow foam in 87% yield,22 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.04(s, 3H), 1.23-1.28(m, 2H),1.84-1.93(m, 1H), 2.08-2.17 (m, 1H), 2.36-2.50 (m, 2H), 2.56-2.63 (m,2H), 2.71-2.77 (q, 1H), 2.85-2.89 (m, 1H), 4.73-4.79(m, 1H),6.53-6.54(d, 1H), 6.60-6.61(d, 1H), 6.66-6.67(d, 1H), 7.22-7.36(m, 10H);LRMS ESI m/z 484 [M+H]⁺

EXAMPLE 695-[(3S)-3-(2-Cyano-5-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of preparation 17 and2-hydroxy-4-methoxybenzonitrile using the same method as that describedfor preparation 36, to afford an orange foam in 36% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.04(s, 3H), 1.21-1.29(m, 2H),1.89-1.98(m, 1H), 2.10-2.20(m, 1H), 2.35-2.51(m, 2H), 2.57-2.68(m, 2H),2.73-2.83(m, 1H), 2.91-2.99(m, 1H), 3.86(s, 3H), 4.88-4.91(m, 1H),6.51(d, 1H), 6.61-6.64(dd, 1H), 7.20-7.39(m, 10H), 7.48-7.50 (d, 1H);LRMS ESI m/z 498 [M+H]⁺

EXAMPLE 705-{(3S)-3-[(7-Hydroxy-2-naphthyl)oxy]pyrrolidin-1-yl}-5-methyl-2,2-diphenylhexanamide

Ammonium fluoride (53 mg, 1.44 mmol) was added to a solution of theproduct of preparation 37 (90 mg, 0.144 mmol) in methanol (3 mL) andwater (0.3 mL) and the mixture was heated at 50° C. for 18 hours. Themixture was concentrated in vacuo and the residue purified using aRediSep® silica gel cartridge eluting with dichloromethane:methanol:0.88ammonia (100:0:0 to 90:10:1). Appropriate fractions were concentrated invacuo and the residue further purified using a RediSep® silica gelcartridge eluting with dichloromethane:methanol:0.88 ammonia (100:0:0 to93:7:0.7) to afford the title compound as a colourless gum in 6% yield,4.5 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.96(s, 3H), 1.06(s, 3H), 1.19-1.30(m, 2H),1.88-1.98(m, 1H), 2.11-2.23(m, 1H), 2.34-2.52(m, 2H), 2.54-2.64(m, 1H),2.64-2.68(m, 1H), 2.72-2.82(m, 1H), 2.85-2.91(m, 1H), 4.82-4.89(m, 1H),6.77-6.83(m, 1H), 6.85-6.87(m, 1H), 6.88-6.91(m, 1H), 6.98-7.01 (m, 1H),7.15-7.35(m, 10H), 7.54-7.62(m, 2H); LRMS APCI m/z 509 [M+H]⁺

EXAMPLE 715-[(3S)-3-(4-Phenylphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

A solution of triphenylphosphine (143 mg, 0.546 mmol) in tetrahydrofuran(1 mL) and di-isopropylazodicarboxylate (0.11 mL, 0.546 mmol) were addedto a solution of the product of preparation 17 (100 mg, 0.273 mmol) intetrahydrofuran (1 mL) and the mixture was stirred at room temperaturefor 15 minutes. 4-Phenylphenol (93 mg, 0.546 mmol) was added and themixture was stirred at room temperature for 18 hours. Furthertriphenylphosphine (143 mg, 0.546 mmol) and di-isopropylazodicarboxylate(0.11 mL, 0.546 mmol) were added and the solution was stirred at roomtemperature for 72 hours. The mixture was concentrated in vacuo and theresidue purified by column chromatography on silica gel, eluting withdichloromethane:methanol (100:0 to 95:5) to afford the title compound asa colourless oil in 28% yield, 40 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 3H), 1.07(s, 3H), 1.23-1.26(m, 2H),1.90-1.98(m, 1H), 2.10-2.19(m, 1H), 2.39-2.46(m, 2H), 2.58-2.68(m, 2H),2.75-2.89(m, 2H), 4.80-4.84(m, 1H), 6.88-6.90(d, 2H), 7.20-7.41(m, 13H),7.49-7.56(dd, 4H); LRMS APCI m/z 519 [M+H]⁺

EXAMPLE 725-[(3R)-3-(3-chloro-4-hydroxyphenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 0.16 mL, 0.158 mmol) was addedto a solution of the product of example 28 (20 mg, 0.039 mmol) indichloromethane (3 mL) and the mixture was stirred at room temperaturefor 72 hours. The reaction mixture was quenched via dropwise addition of0.88 ammonia (5 mL) and stirred for 24 hours. The aqueous layer wasseparated and extracted with dichloromethane (3×20 mL). The combinedorganic layers were concentrated in vacuo and the residue was purifiedby column chromatography on silica gel, eluting with ethylacetate:methanol:0.88ammonia (100:0:0 to 95:5:0.5) to afford acolourless gum. This was further purified by HPLC using a CurosilPFP-Acid 150*21.2 stationary phase, eluting with 0.1% Formic acid(aq):(acetonitrile+0.1% Formic acid), 95:5 to 0:100. Appropriatefractions were concentrated in vacuo and the residue was partitionedbetween dichloromethane (15 ml) and water (5 ml), and the aqueous layerwas separated and extracted with further dichloromethane (2×15 ml). Thecombined organic layers were washed with sodium hydroxide solution (1M,5 ml), brine (10 ml) and concentrated in vacuo. The residue was furtherpurified by preparative thin layer chromatography eluting withdichloromethane:methanol:0.88ammonia (90:10:1). Clean product bands werewashed from the silica gel using dichloromethane:methanol:0.88ammonia(95:5:0.5), filtered and concentrated in vacuo to afford the titlecompound as a colourless gum in 16% yield, 3 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.18(s, 3H), 1.22(s, 3H), 1.28-1.30(m, 2H),1.39-1.44(m, 2H), 2.08-2.14(m, 2H), 2.42-2.47(m, 2H), 3.04-3.27(m, 2H),4.82-4.87(m, 1H), 6.66-6.70(m, 1H), 6.82-6.87(m, 2H), 7.25-7.38(m, 10H);LRMS APCI m/z 493 [M+H]⁺491

EXAMPLE 735-[(3R)-3-(3-Fluoro-5-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Diisopropyl azodicarboxylate (160 μL, 0.822 mmol) was added in threeportions to an ice-cooled solution of triphenyl phosphine (215 mg, 0.822mmol), the product of preparation 23 (175 mg, 1.232 mmol) and theproduct of preparation 16 (150 mg, 0.411 mmol) in tetrahydrofuran (7 mL)and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated in vacuo and residue purified using anIsolute® SCX-2 cartridge, eluting with methanol followed by 2M ammoniain methanol. Basic fractions were concentrated in vacuo to afford thetitle compound as a pale brown foam in 75% yield, 150 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.03(s, 3H), 1.21-1.26(m, 2H),1.81-1.89(m, 1H), 2.06-2.15(m, 1H), 2.38-2.46(m, 2H), 2.50-2.61(m, 2H),2.67-2.72(m, 1H), 2.78-2.85(m, 1H), 3.74(s, 3H), 4.69-4.74(m, 1H),6.14-6.19(m, 2H), 6.24-6.28(m, 1H), 7.21-7.36(m, 10H); LRMS ESI m/z 491[M+H]⁺

EXAMPLE 745-[(3R)-3-(3-Fluoro-5-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenyl-hexanamide

Boron tribromide (1M in dichloromethane, 1.2 mL, 1.224 mmol) was addedto an ice-cooled solution of the product of example 73 (150 mg, 0.306mmol) in dichloromethane (4 mL) and the mixture was stirred at roomtemperature for 18 hours. The reaction was quenched with 0.88 ammoniasolution and stirred at room temperature for 2 hours. The reactionmixture was adjusted to pH 8 by dropwise addition of 2N hydrochloricacid (aq) and extracted with dichloromethane (3×10 mL). The combinedorganic layers were dried over sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, affordedthe title compound as a pale brown foam in 49% yield, 71 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.01(s, 3H), 1.05(s, 3H), 1.24-1.28(m, 2H),1.85-1.92(m, 1H), 2.07-2.15(m, 1H), 2.40-2.45(m, 2H), 2.59-2.67(m, 2H),2.73-2.79(q, 1H), 2.87-2.91(m, 1H), 468-4.72(m, 1H), 6.03-6.12(m, 3H)7.21-7.26(m, 2H), 7.28-7.32(m, 4H), 7.33-7.37(m, 4H); LRMS ESI m/z 477[M+H]⁺, 475 [M−H]⁻

EXAMPLE 755-[(3R)-3-(2-Fluoro-3-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Diisopropyl azodicarboxylate (160 μL, 0.822 mmol) was added in threeportions to an ice-cooled solution of triphenyl phosphine (215 mg, 0.822mmol), the product of preparation 26 (160 mg, 1.127 mmol) and productfrom preparation 16 (150 mg, 0.411 mmol) in tetrahydrofuran (7 mL) andthe mixture was stirred at 0° C. to room temperature for 16 hours.Additional triphenyl phosphine (215 mg, 0.822 mmol) and diisopropylazodicarboxylate (160 μL, 0.822 mmol) were added and the mixture stirredfor a further 48 hours. The reaction mixture was concentrated in vacuoand the residue purified using an Isolute® SCX-2 cartridge, eluting withmethanol followed by 2M ammonia in methanol. Basic fractions wereconcentrated in vacuo to afford the title compound as a pale brown foamin 75% yield, 145 mg.

LRMS ESI m/z 491 [M+H]⁺

EXAMPLE 765-[(3R)-3-(2-Fluoro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 1.1 mL, 1.224 mmol) was addedto an ice-cooled solution of the product of example 75 (140 mg, 0.286mmol) in dichloromethane (4 mL) and the mixture was stirred at roomtemperature for 2 hours. The reaction was quenched with 0.88 ammoniasolution and stirred at room temperature for 16 hours. The reactionmixture was adjusted to pH 8 by dropwise addition of 2N hydrochloricacid (aq) and extracted with dichloromethane (2×10 mL). The combinedorganic layers were dried over sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, affordedthe title compound as a pale yellow foam in 15% yield, 20 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.04(s, 3H), 1.25-1.28(m, 2H),1.85-1.93(m, 1H), 2.06-2.12(m, 1H), 2.42-2.46(m, 2H), 2.54-2.60(m, 1H),2.65-2.75(m, 2H), 2.85-2.90(q, 1H), 4.74-4.78(m, 1H), 6.38-6.42(t, 1H),6.49-6.53(t, 1H), 6.80-6.85(t, 1H), 7.22-7.25(m, 2H), 7.28-7.32(m, 4H),7.35-7.38(m, 4H); LRMS ESI m/z 477 [M+H]⁺475 [M−H]⁻

EXAMPLE 775-[(3R)-3-(2-Chloro-3-methoxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Diisopropyl azodicarboxylate (118 μL, 0.606 mmol) was added in threeportions to an ice-cooled solution of triphenyl phosphine (160 mg, 0.606mmol), the product of preparation 21 (120 mg, 0.757 mmol) and productfrom preparation 16 (111 mg, 0.411 mmol) in tetrahydrofuran (7 mL) andthe mixture was stirred at 0° C. to room temperature for 3 hours.Additional triphenyl phosphine (160 mg, 0.606 mmol), and diisopropylazodicarboxylate (118 μL, 0.606 mmol) were added and the mixture stirredfor a further 16 hours. The reaction mixture was concentrated in vacuoand residue purified using an Isolute® SCX-2 cartridge, eluting withmethanol followed by 2M ammonia in methanol. Basic fractions wereconcentrated in vacuo to afford the title compound as a pale brown foamin 82% yield, 124 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.05(s, 3H), 1.24-1.29(m, 2H),1.85-1.97(m, 1H), 2.05-2.15(m, 1H), 2.43-2.47(m, 2H), 2.58-2.64(m, 1H),2.66-2.72(m, 1H), 2.73-2.80(m, 1H), 2.89-2.95(m, 1H), 3.85(s, 3H),4.79-4.81(m, 1H), 6.55-6.57(d, 1H), 6.67-6.70(d, 1H), 7.15-7.19(t, 1H),7.21-7.24(m, 2H), 7.27-7.31(m, 4H), 7.34-7.38(m, 4H); LRMS ESI m/z 507[M+H]⁺

EXAMPLE 785-[(3R)-3-(2-Chloro-3-hydroxy-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 77, usingthe same method as that described for example 74, to afford a paleorange foam in 36% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.03(s, 3H), 1.07(s, 3H), 1.27-1.32(m, 2H),1.92-1.99(m, 1H), 2.06-2.14(m, 1H), 2.43-2.47(m, 2H), 2.65-2.71(m, 1H),2.74-2.78(d, 1H), 2.80-2.86(q, 1H), 2.96-3.00(m, 1H), 4.79-4.82(m, 1H),6.41-6.43(dd, 1H), 6.53-6.55(dd, 1H), 7.00-7.04(t, 1H), 7.21-7.25(m,2H), 7.28-7.32(m, 4H), 7.36-7.39(m, 4H); LRMS ESI m/z 493 [M+H]⁺491[M−H]hu −

EXAMPLE 795-[(3R)-3-(4-Chloro-3-hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Hydrochloric acid (4M in dioxan, 4 ml) and water (0.5 ml) were added tothe product of preparation 44 (161 mg, 0.295 mmol) and the mixture washeated under reflux for 30 minutes. The reaction mixture was then cooledto room temperature and partitioned between ethyl acetate (20 mL) andsaturated aqueous sodium hydrogen carbonate solution (20 mL). Theaqueous layer was separated, extracted with further ethyl acetate (20mL) and the combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with dichloromethane:methanol:0.88 ammonia,95:5:0.5 to 90:10:1, to afford the title compound as a pale brown foamin 19% yield, 29 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.01(s, 3H), 1.02(s, 3H), 1.24-1.28(m, 2H),1.75-1.82(m, 1H), 1.87-1.94(m, 1H), 2.40-2.44(m, 2H), 2.51-2.60(m, 2H),2.63-2.69(q, 1H), 2.73-2.77(q, 1H), 3.98-4.03(m, 1H), 4.34(s, 2H),6.70-6.73(dd, 1H), 6.87-6.88(d, 1H), 7.18-7.21(d, 1H), 7.22-7.26(m, 2H),7.29-7.33(m, 4H), 7.35-7.38(m, 4H); LRMS APCI m/z 505 [M−H]⁻

EXAMPLE 805-[(3R)-3-(3-methoxy-4-chloro-phenoxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

Sodium hydride (60% dispersion in mineral oil, 60 mg, 1.466 mmol) wasadded to an ice-cooled solution of the product of preparation 20 (170mg, 0.489 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred at 0° C. for 30 minutes. 2-chloro-5-fluoro-anisole (73 μl, 0.586mmol) was added and the mixture was stirred for 18 hours at roomtemperature. The mixture was then heated at 60° C. for 6 hours. Themixture was cooled to room temperature, further sodium hydride (60%dispersion in mineral oil, 60 mg, 1.466 mmol) was added and heatingcontinued at 60° C. for 18 hours. The solution was cooled to 0° C.,further sodium hydride (60% dispersion in mineral oil, 100 mg, 2.443mmol) was added and the solution stirred for 30 minutes. Additional2-chloro-5-fluoro-anisole (122 μl, 0.977 mmol) was added and mixtureheated at 80° C. for 18 hours. The reaction mixture was then cooled toroom temperature, quenched with water (3 mL), concentrated in vacuo andthe aqueous residue was partitioned between ethyl acetate (10 mL) andwater (5 mL). The aqueous layer was separated and extracted with furtherethyl acetate (2×10 mL). The combined organic layers were washed withbrine (10 mL), dried over sodium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith ethyl acetate:methanol:0.88ammonia, 99:1:0.1, to afford the titlecompound as a colourless gum in 34% yield, 80 mg.

¹HNMR(400 MHz, —CD₃OD) δ: 1.03(s, 3H), 1.08(s, 3H), 1.44-1.49(m, 2H),1.88-1.95(m, 1H), 2.12-2.21(m, 1H), 2.49-2.54(m, 2H), 2.56-2.62(m, 1H),2.68-2.70(d, 1H), 2.76-2.82(m, 1H), 2.85-2.89(m, 1H), 3.80(s, 3H),4.79-4.81(m, 1H), 6.39-6.42(d, 1H), 6.54(s, 1H), 7.16-7.20(d, 1H),7.26-7.42(m, 10H); LRMS APCI m/z 489 [M+H]⁺

EXAMPLE 815-[(3R)-3-(3-methoxy-4-chloro-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Potassium hydroxide (185 mg, 3.275 mmol) was added to a solution of theproduct of example 80 (80 mg, 0.163 mmol) in 3-methyl-3-pentanol (3 mL)and the mixture was heated under reflux for 24 hours. Further potassiumhydroxide (93 mg, 1.638 mmol) was added and mixture heated at reflux fora further 5 hours. The reaction mixture was then cooled to roomtemperature, concentrated in vacuo and the residue was partitionedbetween ethyl acetate (15 mL) and water (10 mL). The aqueous layer wasseparated, extracted with further ethyl acetate (15 mL) and the combinedorganic layers were dried over sodium sulfate and concentrated in vacuo.

The residue was purified by column chromatography indichloromethane:methanol:0.88 ammonia 97:3:0.3 to 94:6:0.6, to affordthe title compound as a white foam in 64% yield, 53 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.98(s, 3H), 1.05(s, 3H), 1.20-1.26(m, 2H),1.84-1.93(m, 1H), 2.07-2.16(m, 1H), 2.34-2.49(m, 2H), 2.53-2.65(m, 2H),2.70-2.77(m, 1H), 2.81-2.88(m, 1H), 3.80(s, 3H), 4.74-4.79(m, 1H),6.36-6.38(dd, 1H), 6.51-6.52(d, 1H), 7.18-7.20(d, 1H), 7.21-7.35(m,10H); LRMS APCI m/z 507 [M+H]⁺

EXAMPLE 825-[(3R)-3-(3-hydroxy-4-chloro-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 0.4 mL, 0.4 mmol) was added toan ice-cooled solution of the product of example 81 (50 mg, 0.099 mmol)in dichloromethane (2 mL) and the mixture was stirred at roomtemperature for 18 hours. Further boron tribromide (1M indichloromethane, 0.2 mL, 0.2 mmol) was added and the mixture stirred atroom temperature for a further 3 hours. The reaction was quenched with0.88 ammonia solution and stirred at room temperature for 1 hour. Thereaction mixture was acidified to pH 6 by dropwise addition of 2Nhydrochloric acid (aq) and extracted with dichloromethane (2×10 ml). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo. Purification of the residue by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 97:3:0.3 to94:6:0.6, afforded the title compound as a white foam in 70% yield, 34mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.06(s, 3H), 1.24-1.28(m, 2H),1.83-1.93(m, 1H), 2.06-2.15(m, 1H), 2.35-2.47(m, 2H), 2.60-2.68(m, 2H),2.74-2.81(m, 1H), 2.87-2.91(m, 1H), 4.68-4.73(m, 1H), 6.28-6.31(dd, 1H),6.40-6.41(d, 1H), 7.10-7.12(d, 1H), 7.22-7.35(m, 10H); LRMS ESI m/z 493[M+H]⁺491 [M−H]⁻

EXAMPLE 835-[(3R)-3-(3-hydroxy-4-cyano-phenoxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Ammonium formate (44 mg, 0.698 mmol) and palladium hydroxide (20% oncarbon, 8 mg) were added to a solution of the product of preparation 45(40 mg, 0.070 mmol) in ethanol (2 mL) and the mixture was stirred atreflux for 20 minutes. The reaction was cooled, the catalyst removed byfiltration over Arbocel® and the filtrate concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 90:10:1,afforded the title compound as a white foam in 55% yield, 18 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 3H), 1.06(s, 3H), 1.24-1.28(m, 2H),1.87-1.94(m, 1H), 2.09-2.18(m, 1H), 2.35-2.49(m, 2H), 2.61-2.71(m, 2H),2.75-2.82(q, 1H), 2.91-2.95(q, 1H), 4.76-4.79(m, 1H), 6.32-6.35(m, 2H),7.21-7.36(m, 11H); LRMS APCI m/z 484 [M+H]⁺

EXAMPLE 845-[(3S)-3-(3-methoxy-benzyloxy)pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Sodium hydride (60% dispersion in mineral oil, 26 mg, 0.638 mmol) wasadded to an ice-cooled solution of the product of preparation 18 (185mg, 0.532 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred at 0° C. for 60 minutes. 3-Methoxybenzyl bromide (128 mg, 0.638mmol) was added and the mixture was stirred for 3 hours at roomtemperature. Additional 3-methoxybenzyl bromide (160 mg, 0.797 mmol) wasadded and the mixture stirred for a further 2 hours. The reactionmixture was quenched with water (3 mL), concentrated in vacuo and theaqueous residue was partitioned between ethyl acetate (20 mL) and water(10 mL). The aqueous layer was separated and extracted with furtherethyl acetate (2×10 mL). The combined organic layers were concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane to afford a colourless oil, 180 mg.

Potassium hydroxide (430 mg, 7.692 mmol) was added to a solution of thiscolourless oil (180 mg, 0.385 mmol) in 3-methyl-3-pentanol (5 mL) andthe mixture was heated under reflux for 24 hours. The reaction mixturewas cooled to room temperature, concentrated in vacuo and the residuewas partitioned between ethyl acetate (20 mL) and water (10 mL). Theaqueous layer was separated, extracted with further ethyl acetate (10mL) and the combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by columnchromatography, eluting initially with pentane, thendichloromethane:methanol:0.88 ammonia 95:5:0.5 up to 90:10:1, to affordthe title compound as a white foam in 16% yield, 40 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.01(s, 3H), 1.03(s, 3H), 1.26-1.30(m, 2H),1.77-1.85(m, 1H), 1.88-1.95(m, 1H), 2.40-2.45(m, 2H), 2.53-2.72(m, 3H),2.75-2.79(m, 1H), 3.76(s, 3H), 4.00-4.05(m, 1H), 4.41 (s, 2H),6.80-6.83(d, 1H), 6.86-6.88(m, 2H), 7.16-7.37(m, 11H); LRMS ESI m/z 487[M+H]⁺

EXAMPLE 855-[(3R)-3-(2-Chloro-3-hydroxy-benzyloxy)-pyrrolidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of preparation 49,using the same method as that described for example 79, to afford awhite foam in 34% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.11(s, 3H), 1.13(s, 3H), 1.34-1.38(m, 2H),1.90-2.02(m, 2H), 2.41-2.45(m, 2H), 2.83-3.02(m, 4H), 4.14-4.18(m, 1H),4.49-4.57(m, 2H), 6.84-6.87(dd, 1H), 6.91-6.93(d, 1H), 7.06-7.10(t, 1H),7.24-7.27(m, 2H), 7.30-7.38(m, 8H); LRMS APCI m/z 505 [M−H]⁻

EXAMPLE 865-Methyl-5-(4-phenoxypiperidin-1-yl)-2,2-diphenylhexanenitrile

A solution of the product of preparation 50 (9.03 g, 21 mmol) intetrahydrofuran (270 mL) was cooled to −20° C. Zirconium tetrachloride(9.91 g, 43 mmol) was added and the reaction mixture was stirred at −20°C. for 1 hour. Methyl magnesium chloride (3M in tetrahydrofuran, 63.8mL, 191 mmol) was then added dropwise and the mixture was stirred for 1hour, with the temperature maintained below −10° C. The reaction wasquenched with ethanol (20 mL), concentrated in vacuo and the residue waspartitioned between 2N sodium hydroxide solution (200 mL) and ethylacetate (250 mL). The aqueous layer was separated and extracted withethyl acetate (2×200 mL), and the combined organic solution was driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel, eluting withpentane:ethyl acetate, 75:25 to 67:33. The appropriate fractions wereevaporated under reduced pressure and the residue was further purifiedby using an Isolute® SCX-2 cartridge, methanol followed by 1M ammonia inmethanol, to afford the title compound as a yellow gum in a 41% yield(3.83 g).

¹HNMR(400 MHz, CDCl₃) δ: 1.04(s, 6H), 1.54-1.58(m, 2H), 1.71-1.80(m,2H), 1.99-2.02(m, 2H), 2.25(m, 2H), 2.53-2.57(m, 2H), 2.70-2.75(m, 2H),4.22-4.28(m, 1H), 6.92-6.96(m, 3H), 7.28-7.32(m, 4H), 7.35-7.39(m, 4H),7.45-7.47(m, 4H); LRMS APCI m/z 439 [M+H]⁺

EXAMPLE 875-{4-[(3-Bromobenzyl)oxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of preparation 53,using the same method as that described for example 86, as a yellow gumin 33% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.98(s, 6H), 1.46-1.60(m, 4H), 1.88-1.91(m,2H), 2.04-2.09(m, 2H), 2.46-2.50(m, 2H), 2.65-2.68(m, 2H), 3.28-3.34(m,1H), 4.50(s, 2H), 7.18-7.42(m, 13H), 7.51 (s, 1H); LRMS ESI m/z 533[M+H]⁺

EXAMPLE 885-{4-[(3-Hydroxybenzyl)oxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

n-Butyl lithium (2.5M in hexanes, 0.18 mL, 0.45 mmol) was added dropwiseto a solution of the product of example 87 (200 mg, 0.38 mmol) intetrahydrofuran (5 mL), cooled to −78° C., and the mixture was stirredfor 15 minutes. Trimethylborate (0.13 mL, 1.13 mmol) was added and themixture was stirred at −78° C. for 30 minutes and at room temperaturefor 2 hours. 4-methylmorpholine N-oxide (132 mg, 1.13 mmol) was addedand the mixture was heated under reflux for 4 hours and stirred at roomtemperature for 18 hours. The reaction mixture was then partitionedbetween ethyl acetate (30 mL) and water (30 mL) and the organic layerwas separated and washed with water (20 mL). The organic solution wasdried over sodium sulfate, concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 100:0.0 to 90:10:1. Theappropriate fractions were evaporated under reduced pressure and theresidue was further purified by preparative tlc, eluting withdichloromethane:methanol:0.88 ammonia, 90:10:1, to afford the titlecompound as a gum in 3% yield, 5 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.02(s, 6H), 1.46-1.58(m, 4H), 1.86-1.90(m,2H), 2.13-2.19(m, 2H), 2.49-2.53(m, 2H), 2.70-2.75(m, 2H), 3.33-3.39(m,1H), 4.45 (s, 2H), 6.67-6.70(m, 1H), 6.77-6.79(m, 2H), 7.12(m, 1H),7.28-7.43(m, 10H); LRMS ESI m/z 469 [M+H]⁺

EXAMPLE 895-[4-(Benzyloxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

n-Butyl lithium (2.5M in hexanes, 0.23 mL, 0.56 mmol) was added dropwiseto a solution of the product of example 87 (200 mg, 0.38 mmol) intetrahydrofuran (8 mL), cooled to −78° C., and the mixture was stirredfor 30 minutes. Carbon dioxide was then passed through the solution,with stirring at −78° C., for 3.5 hours before the mixture was allowedto warm to room temperature. The reaction mixture was concentrated invacuo and the residue was partitioned between ethyl acetate (30 mL) andwater (20 mL). The organic layer was separated, washed with water, driedover magnesium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 100:0:0 to 98:2:0.2, afforded thetitle compound as a by-product, as an off white solid in 68% yield, 116mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.00(s, 6H), 1.45-1.49(m, 2H), 1.50-1.58(m,2H), 1.86-1.90(m, 2H), 2.11-2.17(m, 2H), 2.48-2.53(m, 2H), 2.69-2.72(m,2H), 3.33-3.39(m, 1H), 4.51(s, 2H), 7.29-7.42(m, 15H); LRMS ESI m/z 453[M+H]⁺

EXAMPLE 90 5-Methyl-5-(4-phenoxypiperidin-1-yl)-2,2-diphenylhexanamide

Potassium hydroxide (512 mg, 9.12 mmol) was added to a solution of theproduct of example 86 (200 mg, 0.46 mmol) in 3-methyl-3-pentanol (4 mL)and the mixture was heated Under reflux for 20 hours. The reactionmixture was then cooled to room temperature, concentrated in vacuo andthe residue was partitioned between ethyl acetate (20 mL) and water (20mL). The organic layer was separated, dried over magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 100:0 to 90:10:1, afforded the title compound as a colourlessglass in 93% yield, 193 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.99(s, 6H), 1.25-1.29(m, 2H), 1.60-1.68(m,2H), 1.89-1.93(m, 2H), 2.20-2.25(m, 2H), 2.42-2.46(m, 2H), 2.64-2.68(m,2H), 4.20-4.27(m, 1H), 6.85-6.89(m, 3H), 7.20-7.26(m, 4H), 7.30-7.34(m,4H), 7.37-7.40(m, 4H); LRMS ESI m/z 457 [M+H]⁺

EXAMPLE 915-{4-[(3-Bromobenzyl)oxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 87, usingthe same method as that described for example 90, as a colourless gum in99% yield.

¹HNMR(400 MHz, CD₃OD) δ: 0.97(s, 6H), 1.23-1.27(m, 2H), 1.48-1.57(m,2H), 1.82-1.87(m, 2H), 2.07-2.12(m, 2H), 2.40-2.44(m, 2H), 2.62-2.66(m,2H), 3.29-3.37(m, 1H), 4.48(s, 2H), 7.21-7.42(m, 13H), 7.49(s, 1H); LRMSESI m/z 551 [M+H]⁺

EXAMPLE 925-[4-(Benzyloxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 89, usingthe same method as that described for example 90, as a colourless glassin 79% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.01(s, 6H), 1.26-1.30(m, 2H), 1.57-1.59(m,2H), 1.86-1.89(m, 2H), 2.21(m, 2H), 2.40-2.45(m, 2H), 2.72(m, 2H),3.38(m, 1H), 4.50(s, 2H), 7.23-7.39(m, 15H); LRMS APCI m/z 471 [M+H]⁺

EXAMPLE 935-[4-(2,4-Dichloro-5-hydroxy-phenoxy)-piperidin-1-yl]-5-methyl-2,2-diphenylhexanoicacid amide

Diisopropyl azodicarboxylate (0.05 mL, 0.26 mmol) was added dropwise toa mixture of preparation 54 (50 mg, 0.13 mmol),4,6-dichlorobenzene-1,3-diol (47 mg, 0.26 mmol) and triphenylphosphine(69 mg, 0.26 mmol) in tetrahydrofuran (1 mL) and the mixture left tostir for 7 days at room temperature. The solvent was concentrated invacuo and the residue purified using an Isolute® SCX-2 cartridge,eluting with methanol followed by 1M ammonia in methanol. Theappropriate fractions were combined, evaporated under reduced pressureand the residue further purified by column chromatography on silica gel,eluting with dichloromethane methanol, 98:2 to 95:5, afforded the titlecompound as a colourless glass in 8% yield, 6 mg.

¹HNMR(400 MHz, CD₃OD) δ: 1.04(s, 6H), 1.28-1.32(m, 2H), 1.71-1.78(m,2H), 1.86-1.92(m, 2H), 2.36-2.46(m, 4H), 2.69-2.75(m, 2H), 4.29 (m, 1H),6.57(s, 1H), 7.21-7.39(m, 11H); LRMS ESI m/z 541 [M+H]⁺

EXAMPLE 945-[4-(4-Cyano-2,5-difluoro-phenoxy)-piperidin-1-yl]-5-methyl-2,2-diphenylhexanoicacid amide

Sodium hydride (60% dispersion in mineral oil, 12 mg, 0.29 mmol) wasadded to a solution of the product of preparation 54 (100 mg, 0.26 mmol)in tetrahydrofuran (0.5 mL) at room temperature and allowed to stir for20 minutes before cooling to −70° C. The mixture was added into asolution of 2,4,5-trifluorobenzonitrile (41 mg, 0.26 mmol) intetrahydrofuran (0.5 mL) at −70° C. and stirred for 3 hours. Thereaction was then allowed to warm to room temperature and stirred for afurther 18 hours. The reaction was quenched with water (5 drops) and thesolvent evaporated in vacuo. The residue was partitioned between ethylacetate (40 mL) and water (20 mL), the organic layer was separated andwashed with brine (20 mL). The organic phase was dried over magnesiumsulfate, concentrated in vacuo and the residue purified by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 100:0:0 to 90:10:1. The appropriate fractions were evaporatedunder reduced pressure to afford the title compound as a colourlessglass in 40% yield, 54 mg.

¹HNMR(400 MHz, CD₃OD) δ: 0.99(s, 6H), 1.25-1.29(m, 2H), 1.66-1.75(m,2H), 1.92-1.97(m, 2H) 2.25-2.30(m, 2H) 2.42-2.46(m, 2H), 4.43-4.49(m,1H), 7.13-7.52(m, 12H); LRMS APCI m/z 518 [M+H]⁺

EXAMPLE 955-[4-(3-hydroxyphenoxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Diisopropyl azodicarboxylate (0.23 mL, 1.20 mmol) was added dropwise toan ice cold solution of the product of preparation 54 (226 mg, 0.594mmol), resorcinol (196 mg, 1.71 mmol) and triphenylphosphine (312 mg,1.19 mmol) in tetrahydrofuran (2 mL) and the mixture stirred at roomtemperature for 12 hours. The solvent was removed under reduced pressureand the residue purified using an Isolute® SCX-2 cartridge, eluting withmethanol, then with 1M ammonia in methanol. Basic fractions wereconcentrated in vacuo and further purified by chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 98:2:0.2 to95:5:0.5. Appropriate fractions were concentrated in vacuo and half ofthe residue obtained (55 mg) was further purified by preparative thinlayer chromatography using a silica coated plate and eluting withdichloromethane:methanol:0.88ammonia 80:20:2 to afford the titlecompound as a gum in 14% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.05 (s, 6H), 1.30-1.34 (m, 2H), 1.66-1.74 (m,2H), 1.91-1.96 (m, 2H), 2.34-2.47 (m, 4H), 2.70-2.79 (m, 2H), 4.21-4.27(m, 1H), 6.32-6.38 (m, 3H), 7.00-7.05 (m, 1H), 7.23-7.40 (m, 10H); LRMSAPCI m/z 473 [M+H]⁺

EXAMPLE 965-[4-(3-hydroxy-2-methylphenoxy)piperidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Diisopropyl azodicarboxylate 0.1 mL, 0.53 mmol) was added dropwise to asolution of the product of preparation 54 (100 mg, 0.263 mmol),2-methyl-resorcinol (130 mg, 1.05 mmol) and triphenylphosphine (139 mg,0.53 mmol) in tetrahydrofuran (2 mL) and the mixture stirred at roomtemperature for 12 hours. The solvent was removed under reduced pressureand purified using an Isolute® SCX-2 cartridge, eluting with methanol,then with 1M ammonia in methanol. Basic fractions were concentrated invacuo and further purified by chromatography on silica gel, eluting withdichloromethane:methanol:0.88ammonia, 98:2:0.2 to 95:5:0.5. Appropriatefractions were concentrated in vacuo and the residue further purifiedusing a Phenomenex Curosil PFP column (21.2*150 mm dimensions) on apreparative Agilent 1100 HPLC. The two mobile phases were 0.1% v/vFormic acid (aq) (A) and 0.1% v/v Formic acid in acetonitrile (B),eluting with a gradient of 20-80% B over 18 minutes at a flow rate of 18ml/min. The peaks were detected using a UV detector at 225 nm andappropriate fractions concentrated in vacuo to afford the title compoundas a gum in 9% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.06 (s, 6H), 1.28-1.34 (m, 2H), 1.71-1.81 (m,2H), 1.89-1.94 (m, 2H), 2.02 (s, 3H), 2.37-2.46 (m, 4H), 2.68-2.77 (m,2H), 4.24-4.31 (m, 1H), 6.37-6.41 (m, 2H), 6.86-6.90 (m, 1H), 7.23-7.40(m, 10H); LRMS APCI m/z 487 [M+H]⁺

EXAMPLE 975-{4-[(3′-hydroxybiphenyl-3-yl)methoxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

1,1′-Bis(diphenylphosphino)ferrocenedichloro palladium(II) (8 mg, 0.09mmol) was added to a suspension of the product of example 87 (100 mg,0.19 mmol), 3-hydroxyphenylboronic acid (52 mg, 0.038 mmol) and sodiumcarbonate (40 mg, 0.038 mmol) in tetrahydrofuran (5 mL) and water (1 mL)and the mixture was heated at 60° C. for 12 hours. The suspension wasallowed to cool to room temperature and then evaporated to dryness underreduced pressure. The residue was purified by chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 99:1:0 to98:2:0.2; to give the title compound as a gum in 72% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.09 (s, 6H), 1.52-1.56 (m, 2H), 1.61-1.68 (m,2H), 1.93-1.96 (m, 2H), 2.24-2.42 (m, 2H), 2.51-2.55 (m, 2H), 2.81-2.84(m, 2H), 3.45-3.49 (m, 1H), 4.58 (s, 2H), 6.75-6.78 (m, 1H), 7.02-7.07(m, 2H), 7.21-7.43 (m, 13H), 7.47-7.50 (m, 1H), 7.54 (s, 1H); LRMS ESIm/z 545 [M+H]⁺

EXAMPLE 985-{4-[(3′-hydroxybiphenyl-3-yl)methoxy]piperidin-1-yl}-5-methyl-2,2-diphenylhexanamide

A suspension of the product of example 97 (70 mg, 0.13 mmol) andpowdered potassium hydroxide (144 mg, 2.57 mmol) in 3-methyl-4-pentanol(4 mL) was heated under reflux for 36 hours. The reaction mixture wasallowed to cool to room temperature and the solvent removed underreduced pressure. The residue was partitioned between ethyl acetate (30mL) and water (20 mL). The organic layer was separated, dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 90:10:1. Appropriatefractions were concentrated in vacuo and the residue further purified bychromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 98:2:0.2 to 95:5:0.5, to afford the title compound as a gum in21% yield.

¹HNMR(400 MHz, CD₃OD) δ: 1.05 (s, 6H), 1.22-1.35 (m, 2H), 1.62-1.68 (m,2H), 1.85-1.93 (m, 2H), 2.35-2.45 (m, 4H), 2.78-2.82 (m, 2H), 3.43-3.49(m, 1H), 4.57 (s, 2H), 6.75-6.78 (m, 1H), 7.02-7.07 (m, 2H), 7.21-7.40(m, 13H), 7.47-7.50 (m, 1H), 7.54 (s, 1H); LRMS APCI m/z 563 [M+H]⁺

EXAMPLE 995-[3-(3-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

A mixture of the product of preparation 57 (500 mg, 1.21 mmol), caesiumcarbonate (1.18 g, 3.64 mmol) and 3-methoxyphenol (0.41 mL, 3.64 mmol)in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue waspartitioned between diethyl ether (50 mL) and water (20 mL). The aqueouslayer was separated, extracted with diethyl ether (2×30 mL) and thecombined organic solution was dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with pentane:ethyl acetate, 90:10 to 75:25 thendichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5, to affordthe title compound as a colourless gum in 71% yield, 380 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.90-1.03(m, 6H), 1.31-1.44(m, 2H),2.41-2.56(m, 2H), 3.07-3.24(m, 2H), 3.42-3.54(m, 2H), 3.77(s, 3H),4.63-4.74(m, 1H), 6.28-6.38(m, 2H), 6.48-6.55(m, 1H), 7.26-7.49(m, 11H);LRMS APCI m/z 441 [M+H]⁺

EXAMPLE 1005-[3-(3-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Potassium hydroxide (215 mg; 3.83 mmol) was added to a solution of theproduct of example 99 (85 mg, 0.19 mmol) in 3-methyl-3-pentanol (5 mL)and the mixture was heated under reflux for 24 hours. The reactionmixture was then cooled to room temperature, concentrated in vacuo andthe residue was partitioned between ethyl acetate (20 mL) and water 15mL). The aqueous layer was separated, extracted with ethyl acetate (20mL) and the combined organic solution was dried over magnesium sulfateand concentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 100:0:0 to 93:7:0.7, afforded the title compound as acolourless gum in 74% yield, 65 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.92(s, 6H), 1.12-1.23(m, 2H), 2.40-2.50(m,2H), 3.10-3.25(m, 2H), 3.44-3.58(m, 2H), 3.78(s, 3H), 4.62-4.72(m, 1H),6.30-6.38(m, 2H), 6.47-6.54(m, 1H), 7.10-7.18(m, 1H), 7.22-7.45(m, 10H);LRMS ESI m/z 459 [M+H]⁺

EXAMPLE 1015-[3-(Benzyloxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.60 mmol) wasadded to an ice-cooled solution of the product of preparation 56 (166mg, 0.50 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred for 30 minutes allowing the temperature to rise to 25° C. Thereaction mixture was then re-cooled to 0° C., benzyl bromide (89 μL,0.75 mmol) was added and the mixture was stirred at 0° C. for 30minutes. The reaction was quenched with 2M hydrochloric acid (2 mL),basified to pH 8 with saturated sodium hydrogen carbonate solution andextracted with ethyl acetate (3×50 mL). The combined organic solutionwas dried over magnesium sulfate, concentrated in vacuo and the residuewas purified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 100:0:0 to 97:3:0.3, to affordthe title compound as a colourless oil in 65% yield, 137 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.91(s, 6H), 0.90-0.97(m, 2H), 2.40-2.48(m,2H), 2.97-3.06(m, 2H), 3.21-3.30(m, 2H), 4.07-4.17(m, 1H), 4.41(s, 2H),7.26-7.46(m, 15H); LRMS APCI m/z 425 [M+H]⁺

EXAMPLE 1025-[3-(Benzyloxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 101, usingthe same method as that described for example 100, as a colourless gumin 77% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.89(s, 6H), 1.05-1.13(m, 2H), 2.32-2.41(m,2H), 2.95-3.05(m, 2H), 3.15-3.25(m, 2H), 4.02-4.13(m, 1H), 4.39(s, 2H),7.21-7.42(m, 15H); LRMS APCI m/z 443 [M+H]⁺

EXAMPLE 1035-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanenitrile

The title compound was prepared from the product of preparation 65,using the same method as that described for preparation 62, as acolourless oil in 38% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.34-1.41 (m, 2H), 2.43-2.54 (m,2H), 3.15-3.22 (m, 2H), 3.45-3.55 (m, 2H), 4.65-4.75 (m, 1H), 6.73-6.78(m, 2H), 6.90-6.98 (m, 1H), 7.22-7.45 (m, 12H); LRMS APCI m/z 411 [M+H]⁺

EXAMPLE 104 5-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanamide

The title compound was prepared from the product of example 103, usingthe same method as that described for example 100, as a white solid in88% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.91(s, 6H), 1.12-1.20(m, 2H), 2.42-2.48(m,2H), 3.12-3.18(m, 2H), 3.45-3.55 (m, 2H), 4.62-4.73(m, 1H), 5.55(brs,2H), 6.75-6.78(m, 2H), 6.92-6.96(m, 1H), 7.20-7.41(m, 12H); LRMS APCIm/z 429 [M+H]⁺

EXAMPLE 1055-[3-(4-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the product of preparation 57 and4-methoxyphenol, using the same method as that described for example 99,as a colourless gum in 55% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.98(s, 6H), 1.33-1.45(m, 2H), 2.45-2.55(m,2H), 3.14-3.24(m, 2H), 3.42-3.55(m, 2H), 3.78(s, 3H), 4.58-4.68(m, 1H),6.66-6.74(m, 2H), 6.76-6.85(m, 2H), 7.25-7.47(m, 10H); LRMS APCI m/z 441[M+H]⁺

EXAMPLE 1065-[3-(4-Methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Potassium hydroxide (135 mg, 2.41 mmol) was added to a solution of theproduct of example 105 (53 mg, 0.12 mmol) in 3-methyl-3-pentanol (5 mL)and the mixture was heated under reflux for 18 hours. The reactionmixture was then cooled to room temperature, concentrated in vacuo andthe residue was partitioned between ethyl acetate (20 mL) and water (5mL). The aqueous layer was separated, extracted with ethyl acetate (2×20mL) and the combined organic solution was dried over magnesium sulfateand concentrated in vacuo to give a colourless oil in 96% yield, 53 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.92(s, 6H), 1.12-1.23(m, 2H), 2.40-2.50(m,2H), 3.10-3.25(m, 2H), 3.44-3.58(m, 2H), 3.78(s, 3H), 4.62-4.72(m, 1H),6.30-6.38(m, 2H), 6.47-6.54(m, 1H), 7.10-7.18(m, 1H), 7.22-7.45(m, 10H);LRMS ESI m/z 459 [M+H]⁺

EXAMPLE 1075-[3-(4-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The product of example 106 (53 mg, 0.16 mmol) was dissolved indichloromethane (5 mL) and the solution was cooled to 0° C. Borontribromide (1M in dichloromethane, 0.52 mL, 0.52 mmol) was added and thesolution was stirred at 0° C. for 35 minutes. Further boron tribromide(1M in dichloromethane, 0.52 mL, 0.52 mmol) was added and stirringcontinued at 0° C. for 30 minutes. The reaction was then quenched withsaturated sodium hydrogen carbonate solution (20 mL) and stirred at roomtemperature for 18 hours. The aqueous layer was separated, extractedwith ethyl acetate (25 mL) and the combined organic solution was driedover magnesium sulfate and concentrated in vacuo to give a gum. The gumwas re-dissolved in dichloromethane (5 mL) and the solution was cooledto −10° C. Boron tribromide (1M in dichloromethane, 0.52 mL, 0.52 mmol)was added and the mixture was stirred at −10° C. for 1 hour. Thereaction was then quenched with saturated sodium hydrogen carbonatesolution (20 mL) and the organic layer was separated and extracted withethyl acetate (20 mL). The combined organic solution was dried overmagnesium sulfate, concentrated in vacuo and the residue was purified bycolumn chromatography on silica gel, eluting with pentane:ethylacetate/methanol/0.88 ammonia (90/10/1), 75:25 to 50:50, to afford thetitle compound as a colourless foam in 27% yield (14 mg).

¹HNMR(400 MHz, CDCl₃) δ: 0.92(s, 6H), 1.13-1.26(m, 2H), 2.40-2.50(m,2H), 3.08-3.24(m, 2H), 3.42-3.58(m, 2H), 4.52-4.63(m, 1H), 5.50-5.68(brs, 2H), 6.53-6.62(m, 2H), 6.67-6.78(m, 2H), 7.21-7.42(m, 10H); LRMSAPCI m/z 445 [M+H]⁺

EXAMPLE 1085-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 1.75 mL, 1.75 mmol) was addedto an ice-cooled solution of the product of example 100 (200 mg, 0.44mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for1 hour. Further boron tribromide (1M in dichloromethane, 0.5 mL, 0.5mmol) was added and the mixture was stirred at 0° C. for 30 minutes. Thereaction was then quenched with 1M sodium hydroxide solution (5 mL),diluted with dichloromethane (20 mL) and stirred at room temperature for40 minutes. The aqueous layer was separated, extracted with ethylacetate (2×25 mL) and the combined organic solution was dried overmagnesium sulfate and concentrated in vacuo. Purification of the residueby column chromatography on silica gel, eluting with pentane:ethylacetate/methanol/0.88 ammonia (90/10/1), 75:25 to 50:50, afforded thetitle compound as a colourless foam in 91% yield, 176 mg.

¹HNMR(400 MHz, CDCl₃) δ: 1.10(s, 6H), 1.22-1.34(m, 2H), 2.42-2.55(m,2H), 3.28-3.40(m, 2H), 3.65-3.88(m, 2H), 4.70-4.80(m, 1H),5.55-5.70(brs, 2H), 6.23-6.36(m, 2H), 6.45-6.53(m, 1H), 7.03-7.12(m,1H), 7.19-7.39(m, 10H); LRMS ESI m/z 445 [M+H]⁺

EXAMPLE 1095-[3-(2-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

Ammonium formate (25 mg, 0.4 mmol) was added to a mixture of the productof preparation 63 (35 mg, 65 μmol) and 20% Pd(OH)₂/C (10 mg) in ethanol(10 mL) and the mixture was heated under reflux for 2 hours. Thereaction mixture was cooled to room temperature, further ammoniumformate (25 mg, 0.4 mmol) and 20% Pd(OH)₂/C (10 mg) were added and themixture was re-heated under reflux for 2 hours. The reaction mixture wasfiltered through Arbocel®, washing through with methanol, and thefiltrate was concentrated in vacuo. The residue was diluted withsaturated sodium hydrogen carbonate solution extracted with ethylacetate (2×20 mL) and the combined organic solution was dried overmagnesium sulfate and concentrated in vacuo. Purification of the residueby column chromatography on silica gel, eluting with ethylacetate:methanol, 95:5, then afforded the title compound as a colourlessoil in quantitative yield, 30 mg.

¹HNMR(400 MHz, CDCl₃) δ: 1.02(s, 6H), 1.22-1.32(m, 2H), 2.31-2.49(m,2H), 2.57-2.72(m, 2H), 3.98-4.04(m, 1H), 4.15-4.24(m, 2H),5.40-5.70(brm, 2H), 6.77-6.86(m, 4H), 7.22-7.38(m, 10H); LRMS APCI m/z445 [M+H]⁺

EXAMPLE 1105-{3-(2,4-Dichloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

Potassium hydroxide (523 mg, 9.33 mmol) was added to a solution of theproduct of preparation 68 (250 mg, 0.46 mmol) in 3-methyl-3-pentanol (5mL) and the mixture was heated under reflux for 18 hours. The reactionmixture was then cooled to room temperature, concentrated in vacuo andthe residue was partitioned between ethyl acetate (20 mL) and water (20mL). The aqueous layer was separated and extracted with ethyl acetate(20 mL) and the combined organic solution was dried over magnesiumsulphate and concentrated in vacuo. The crude material was treated with4M hydrochloric acid in dioxane (10 mL, 40 mmol) and the solutionstirred at 60° C. for 30 minutes. The dioxane was removed in vacuo andthe residue basified with 0.88 ammonia. The aqueous layer was extractedwith ethyl acetate (2×20 mL). The combined organic solution was driedover magnesium sulphate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol 100:1 to 10:1 to afford the title compound as acolourless oil in 61% yield, 147 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.18-1.25 (m, 2H), 2.41-2.55 (m,2H), 3.32-3.38 (m, 2H), 3.75-3.82 (m, 2H), 4.68-4.75 (m, 1H), 5.65-5.75(m, 1H), 5.95-6.05 (m, 1H), 6.43 (s, 1H), 7-20-7.40 (m, 11H); LRMS APCIm/z 513 [M+H]⁺

EXAMPLE 1115-{3-(4,5-Dichloro-2-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of preparation 70,using the same method as described for example 110, as a colourless oilin 53% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.02 (s, 6H), 1.22-1.30 (m, 2H), 2.35-2.50 (m,2H), 2.60-2.75 (m, 2H), 3.95-4.01 (m, 1H), 4.10-4.25 (m, 2H), 5.40-5.60(m, 2H), 6.92-6.98 (m, 2H), 7-20-7.40 (m, 10H); LRMS ESI m/z 513 [M+H]⁺

EXAMPLE 1125-[3-(4-Chloro-3-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from 4-chloro-3-methoxyphenol (EP230379,p 52) and the product of preparation 57, using the same method as thatdescribed for example 99, as a colourless oil in 85% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.35-1.40 (m, 2H), 2.45-2.53 (m,2H), 3.16-3.20 (m, 2H), 3.45-3.52 (m, 2H), 3.86 (s, 3H), 4.62-4.70 (m,1H), 6.20-6.25 (m, 1H), 6.40-6.43 (m, 1H), 7-18-7.45 (m, 11H); LRMS APCIm/z 475 [M+H]⁺

EXAMPLE 1135-{3-(4-Chloro-3-methoxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 112, usingthe same method as that described for example 100, as a colourless oilin 91% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.85 (s, 6H), 1.08-1.22 (m, 2H), 2.38-2.50 (m,2H), 3.15-3.20 (m, 2H), 3.40-3.55 (m, 2H), 3.85 (s, 3H), 4.60-4.72 (m,1H), 5.30-5.55 (m, 2H), 6.20-6.23 (m, 1H), 6.38-6.41 (m, 1H). 7-18-7.40(m, 11H); LRMS APCI m/z 493 [M+H]⁺

EXAMPLE 1145-{3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 1.75 mL, 1.75 mmol) was addedto an ice-cooled solution of the product of example 113 (180 mg, 0.36mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for1.5 hour. The reaction was then quenched with 0.88 ammonia (30 mL) andthe solution stirred at room temperature for 18 hours. The organic layerwas separated, dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane to dichloromethane/methanol/0.88 ammonia(97:3:0.3), afforded the title compound as a colourless foam in 93%yield, 270 mg

¹HNMR(400 MHz, CDCl₃) δ: 0.85 (s, 6H), 1.08-1.22 (m, 2H), 2.40-2.50 (m,2H), 3.10-3.20(m, 2H), 3.50-3.58 (m, 2H), 4.58-4.66 (m, 1H), 5.45-5.55(m, 1H), 5.75-5.90 (m, 1H), 6.25-6.32 (m, 1H), 6.38-6.40 (m, 1H).7-15-7.40 (m, 11H); LRMS APCI m/z 479 [M+H]⁺

EXAMPLE 1155-[3-(3-Hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The product of preparation 73 (65 mg, 0.131 mmol) was treated with 4Mhydrochloric acid in dioxane (2 mL, 8 mmol), water (0.2 ml) was addedand the solution stirred at 85° C. for 30 minutes. The dioxane wasremoved in vacuo and the residue partitioned between ethyl acetate (25ml) and saturated sodium hydrogen carbonate solution (20 mL). Theaqueous layer was extracted with ethyl acetate (20 mL). The combinedorganic solution was dried over magnesium sulphate and concentrated invacuo. The residue was purified by column chromatography on silica gel,eluting with pentane:ethyl acetate:methanol:0.88 ammonia (90/10/1),75:25 to 50:50, to afford the title compound as a colourless foam in 70%yield, 42 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.90(s, 6H), 1.16-1.25(m, 2H), 2.38-2.48(m,2H), 3.02-3.12 (m, 2H), 3.28-3.40(m, 2H), 4.06-4.17(m, 1H), 4.31 (s,2H), 5.58-5.74 (br s, 2H), 6.72-6.83 (m, 3H), 7.12-7.20(m, 1H),7.21-7.40 (m, 10H); LRMS APCI m/z 459 [M+H]⁺

EXAMPLE 1165-[3-(2-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from the product of preparation 57 and2-chloro-5-methoxyphenol, using the same method as that described forexample 99, as a brown gum in 55% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.96 (s, 6H), 1.31-1.44(m, 2H), 2.40-2.57 (m,2H), 3.14-3.35 (m, 2H), 3.40-3.60 (m, 2H), 3.77(s, 3H), 4.64-4.79 (m,1H), 6.20-6.25 (m, 1H), 6.39-6.47(m, 1H), 7.20-7.48(m, 11H); LRMS APCIm/z 475 [M+H]⁺

EXAMPLE 1175-[3-(2-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 116, usingthe same method as that described for example 100, as a colourless gumin 61% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.11-1.20 (m, 2H), 2.40-2.48 (m,2H), 3.15-3.24 (m, 2H), 3.42-3.55 (m, 2H), 3.76 (s, 3H), 4.64-4.72 (m,1H), 5.48-5.75 (m, 2H), 6.20-6.25 μm, 1H), 6.38-6.45 (m, 1H). 7.20-7.41(m, 11H); LRMS APCI m/z 493 [M+H]⁺

EXAMPLE 1185-[3-(2-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

Boron tribromide (1M in dichloromethane, 1.42 mL, 1.42 mmol) was addedto an ice-cooled solution of the product of example 117 (70 mg, 0.142mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for1 hour. The reaction was then quenched with 0.88 ammonia (20 mL) and thesolution stirred at room temperature for 18 hours. The organic layer wasseparated. The aqueous layer was extracted with dichloromethane (20mls). The combined organic solution was washed with saturated sodiumhydrogen carbonate solution (10 mL) and dried over magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with pentane:ethylacetate:methanol:0.88 ammonia (90/10/1), 85:15 to 50:50. The resultinggum was dissolved in methanol (5 mls) and 1N hydrochloric acid indiethyl ether (0.5 ml) added. The solution was evaporated and the solidrecrystallised from ethyl acetate/methanol to give the title compoundhydrochloride salt as a purple solid in 30% yield, 22 mgs.

¹HNMR(400 MHz, CD₃OD) δ: 1.28 (s, 6H), 1.33-1.44 (m, 2H), 2.40-2.48 (m,2H), 4.02-4.30 (m, 2H), 4.33-4.62 (m, 2H), 4.95-5.06 (m, 1H), 6.20-6.28(m, 1H), 6.44-6.49 (m, 1H), 7-15-7.20 (m, 1H), 7.24-7.41 (m, 10H); LRMSAPCI m/z 479 [M+H]⁺

EXAMPLE 1195-[3-(3-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from 3-fluoro-5-methoxyphenol(WO2005037763, p 95) and the product of preparation 57, using the samemethod as that described for example 99, as a colourless oil in 90%yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.35-1.40 (m, 2H), 2.45-2.53 (m,2H), 3.06-3.15 (m, 2H), 3.40-3.48 (m, 2H), 3.75 (s, 3H), 4.58-4.64 (m,1H), 6.05-6.12 (m, 2H), 6.20-6.26 (m, 1H), 7-22-7.45 (m, 10H); LRMS APCIm/z 459 [M+H]⁺

EXAMPLE 1205-{3-(3-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 119, usingthe same method as that described for example 100, as a colourless oilin 90% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.42-1.55 (m, 2H), 2.40-2.48 (m,2H), 3.06-3.15 (m, 2H), 3.40-3.45 (m, 2H), 3.78 (s, 3H), 4.58-4.66 (m,1H), 5.40-5.55 (m, 2H), 6.03-6.12 (m, 2H), 6.20-6.25 (m, 1H), 7.22-7.45(m, 10H).

EXAMPLE 1215-{3-(3-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 120, usingthe same method as that described for example 108, as a colourless oilin 25% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.20-1.26 (m, 2H), 2.40-2.46 μm,2H), 3.20-3.28 (m, 2H), 3.60-3.65 (m, 2H), 4.64-4.70 (m, 1H), 5.50-5.60(m, 1H), 6.00 (s, 1H), 6.02-6.06 (m, 1H), 6.18-6.23 (m, 1H), 6.25-6.35(m, 1H), 7.20-7.35 (m, 10H); LRMS APCI m/z 463 [M+H]⁺

EXAMPLE 1225-[3-(3-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from 3-chloro-5-methoxyphenol and theproduct of preparation 57, using the same method as that described forexample 99, as a colourless oil in 75% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.35-1.40 (m, 2H), 2.45-2.53(m,2H), 3.06-3.15 (m, 2H), 3.40-3.48 (m, 2H), 3.78 (s, 3H), 4.58-4.66 (m,1H), 6.20 (s, 2H), 6.35 (s, 1H), 6.50 (s, 1H), 7-22-7.45 (m, 10H); LRMSAPCI m/z 475 [M+H]⁺

EXAMPLE 1235-[3-(3-Chloro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 122, usingthe same method as that described for example 100, as a colourless oilin 90% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.15-1.20 (m, 2H), 2.38-2.45 (m,2H), 3.02-3.10 (m, 2H), 3.37-3.43 (m, 2H), 3.75 (s, 3H), 4.55-4.63 (m,1H), 5.40-5.65 (m, 2H), 6.18 (s, 1H), 6.30 (s, 1H), 6.48 (s, 1H),7.20-7.40 (m, 10H); LRMS APCI m/z 493 [M+H]⁺

EXAMPLE 1245-{3-(3-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 123, usingthe same method as that described for example 114, as a colourless oilin 92% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.90 (s, 6H), 1.08-1.18 (m, 2H), 2.35-2.45 (m,2H), 3.06-3.15 (m, 2H), 3.40-3.46 (m, 2H), 4.55-4.60 (m, 1H), 5.45 (brs,2H), 6.15 (s, 1H), 6.25 (s, 1H), 6.40 (s, 1H), 7.20-7.40 (m, 10H)

EXAMPLE 1255-[3-(4-Fluoro-2-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from 4-fluoro-2-methoxyphenol and theproduct of preparation 57, using the same method as that described forexample 99, as a colourless oil in 72% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.35-1.40 (m, 2H), 2.45-2.53 (m,2H), 3.20-3.25 (m, 2H), 3.42-3.48 (m, 2H), 3.83 (s, 3H), 4.58-4.66 (m,1H), 6.53-6.65 (m, 3H), 7-22-7.45 (m, 10H); LRMS APCI m/z 459 [M+H]⁺

EXAMPLE 1265-[3-(4-Fluoro-2-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 125, usingthe same method as that described for example 100, as a colourless oilin 87% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.10-1.18 (m, 2H), 2.40-2.48 (m,2H), 3.15-3.20 (m, 2H), 3.40-3.46 (m, 2H), 3.80 (s, 3H), 4.58-4.66 (m,1H), 5.50-5.75 (m, 2H), 6.48-6.65 (m, 3H), 7-22-7.40 (m, 10H); LRMS APCIm/z 477 [M+H]⁺

EXAMPLE 1275-{3-(4-Fluoro-2-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide

The title compound was prepared from the product of example 126, usingthe same method as that described for example 114, as a colourless oilin 32% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.20-1.28 (m, 2H), 2.35-2.48 (m,2H), 2.56-2.68 (m, 2H), 3.95-3.42 (m, 1H), 4.05-4.18 (m, 1H), 4.18-4.25(m, 1H), 5.40-5.65 (m, 2H), 6.45-6.53 (m, 1H), 6.55-6.60(m, 1H),6.72-6.78(m, 1H), 7.20-7.35(m, 10H); LRMS APCI m/z 463 [M+H]⁺

EXAMPLE 1285-[3-(2,6-Dichloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The product of preparation 78 (150 mg, 0.265 mmol) was treated with 4Mhydrochloric acid in dioxane (5 mL, 20 mmol) and water (0.5 ml) and thesolution stirred at 70° C. for 25 minutes. The dioxane was removed invacuo and the residue partitioned between ethyl acetate (30 ml) andsaturated sodium hydrogen carbonate solution (20 mL). The aqueous layerwas extracted with ethyl acetate (20 mL). The combined organic solutionwas dried over magnesium sulphate and concentrated in vacuo. The residuewas purified by column chromatography on silica gel, eluting withpentane:ethyl acetate/methanol/0.88 ammonia (90/10/1), 5:1 to 1:3, toafford the title compound in 52% yield, 73 mg.

¹HNMR(400 MHz, CDCl₃) δ: 1.22 (s, 6H), 1.44-1.53 (m, 2H), 2.60-2.68 (m,2H), 3.60-3.68 (m, 2H), 4.26-4.37 (m, 2H), 4.57-4.64 (m, 1H), 4.70 (s,2H), 5.48-5.55 (br m, 1H), 5.78-5.84 (br m, 1H), 7.06-7.12 (m, 1H),7.18-7.23 (m, 1H), 7.23-7.38 (m, 10H); LRMS APCI m/z 527[M+H]⁺

EXAMPLE 1294-{1-[3-(3-Methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyronitrile

The title compound was prepared from the product of preparation 84 and3-methoxyphenol, using a similar method to that described in example 99,in 73% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.25-1.38 (m, 2H), 1.40-1.65<m, 6H), 1.66-1.76(m, 2H), 2.46-2.57 (m, 2H), 3.06-3.16 (m, 2H), 3.48-3.57 (m, 2H), 3.78(s, 3H), 4.64-4.72 (m, 1H), 6.34 (s, 1H), 6.33-6.37 (m, 1H), 6.48-6.53(m, 1H), 7.13-7.19 (m, 1H), 7.27-7.46 (m, 10H); LRMS APCI m/z 467 [M+H]⁺

EXAMPLE 1304-{1-[3-(3-Methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide

The title compound was prepared from the product of example 129 using asimilar method to that described for example 106, in 48% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.22-1.70 (m, 10H), 2.46-2.53 (m, 2H),3.07-3.15 (m, 2H), 3.47-3.59 (m, 2H), 3.77 (s, 3H), 4.63-4.73 (m, 1H),5.44-5.60 (br m, 2H), 6.33 (s, 1H), 6.33-6.36 (m, 1H), 6.48-6.53 (m,1H), 7.11-7.18 (m, 1H), 7.20-7.40 (m, 10H); LRMS APCI m/z 485[M+H]⁺

EXAMPLE 1314-{1-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide

The title compound was prepared from the product of example 130 using asimilar method to that described for example 108, in 53% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.31-1.47 (m, 6H), 1.48-1.60 (m, 2H), 1.63-1.77(m, 2H), 2.45-2.54 (m, 2H), 3.22-3.28 (m, 2H), 3.73-3.80 (m, 2H),4.75-4.83 (m, 1H), 5.40-5.55 (br m, 1H), 6.24 (s, 1H), 6.36-6.39 (m,1H), 6.48-6.55 (m, 1H), 6.56-6.67 (br m, 1H), 7.08-7.7.16 (m, 1H),7.17-7.38 (m, 10H); LRMS APCI m/z 471[M+H]⁺

EXAMPLE 1325-[3-(2-Fluoro-3-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from the product of preparation 57 and2-fluoro-3-methoxyphenol (J. Comb. Chem. 2002, 4, 329), using a similarmethod to that described for example 99, in 73% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.34-1.40 cm, 2H), 2.44-2.53 (m,2H), 3.20-3.27 (m, 2H), 3.43-3.52 (m, 2H), 3.88 (s, 3H), 4.65-4.74 (m,1H), 6.34-6.39 (m, 1H), 6.58-6.64 (m, 1H), 6.88-6.95 (m, 1H), 7.25-7.47(m, 10H); LRMS APCI m/z 459 [M+H]⁺

EXAMPLE 1335-[3-(2-Fluoro-3-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 132, usingthe same method as that described for example 100, as a colourless oilin 72% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.17-1.25 (m, 2H), 2.40-2.48 (m,2H), 3.20-3.28 (m, 2H), 3.50-3.60 (m, 2H), 4.65-4.74 (m, 1H), 5.46-5.75(br m, 2H), 6.20-6.27 (m, 1H), 6.56-6.63 (m, 1H), 6.80-6.86 (m, 1H),7.25-7.40 (m, 10H); LRMS APCI m/z 477 [M+H]⁺

EXAMPLE 1345-[3-(2-Fluoro-3-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

Boron tribromide (1M in dichloromethane, 1.5 mL, 1.5 mmol) was added toan ice-cooled solution of the product of example 133 (45 mg, 0.094 mmol)in dichloromethane (5 mL) and the mixture was stirred at 0° C. for 45minutes. The reaction was warmed to room temperature. After 15 min, afurther 1.5 mL boron tribromide was added. After 20 minutes, thereaction was quenched with 0.88 ammonia (20 mL) and the solution stirredat room temperature for 18 hours. The organic layer was separated andwashed with saturated sodium hydrogen carbonate solution (10 mL) anddried over magnesium sulfate and concentrated in vacuo. Purification ofthe residue by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia 100:0:0 to 98:2:0.2 to give thetitle compound in 100% yield (44 mg).

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.17-1.26 (m, 2H), 2.43-2.49 (m,2H), 3.20-3.28 (m, 2H), 3.45-3.60 (m, 2H), 4.65-4.74 (m, 1H), 5.49-5.76(br m, 2H), 6.20-6.27 (m, 1H), 6.57-6.62 (m, 1H), 6.80-6.85 (m, 1H),7.23-7.38 (m, 10H); LRMS APCI m/z 463 [M+H]⁺

EXAMPLE 1355-[3-(2-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from the product of preparation 57 and2-fluoro-5-methoxyphenol (J. Can. Chem. 1988, 66, 1479), using a similarmethod to that described for example 99, in 68% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.36-1.42 (m, 2H), 2.44-2.53 (m,2H), 3.20-3.27 (m, 2H), 3.43-3.52 (m, 2H), 3.77 (s, 3H), 4.65-4.74 (m,1H), 6.27-6.34 (m, 1H), 6.38-6.42 (m, 1H), 6.95-7.02 (m, 1H), 7.25-7.47(m, 10H); LRMS APCI m/z 459 [M+H]⁺

EXAMPLE 1365-[3-(2-Fluoro-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 135, usingthe same method as that described for example 100, as a colourless oilin 96% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12-1.20 (m, 2H), 2.40-2.48 (m,2H), 3.16-3.21 (m, 2H), 3.43-3.50 (m, 2H), 3.76 (s, 3H), 4.60-4.72 (m,1H), 5.46-5.60 (br m, 1H), 5.65-5.75 (br m, 1H), 6.25-6.33 (m, 1H),6.34-6.40 (m, 1H), 6.91-6.99 (m, 1H), 7.22-7.40 (m, 10H); LRMS APCI m/z477 [M+H]⁺

EXAMPLE 1375-[3-(2-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 136 usingthe same method as that described for example 118, as a colourless oilin 51% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.04 (s, 6H), 1.22-1.33 (m, 2H), 2.46-2.57 (m,2H), 3.43-3.55 (m, 2H), 3.92-4.00 (m, 2H), 4.75-4.86 (m, 1H), 5.72-5.82(br m, 1H), 6.35-6.48 (m, 3H), 6.83-6.92 (m, 1H), 7.20-7.38 (m, 10H);LRMS APCI m/z 463 [M+H]⁺

EXAMPLE 1385-[3-(4-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 86,using the same method as that described for example 115, as a colourlessoil in 37% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.88 (s, 6H), 1.15-1.20 (m, 2H), 2.38-2.45 (m,2H), 3.00-3.08 (m, 2H), 3.26-3.36 (m, 2H), 4.03-4.15 (m, 1H), 4.27 (s,2H), 5.55-5.80 (br m, 2H), 6.73-6.78 (m, 1H), 6.95 (s, 1H), 7.20-7.38(m, 11H); LRMS APCI m/z 493 [M+H]⁺

EXAMPLE 1394-{1-[3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide

The title compound was prepared from the product of preparation 88,using the same method as that described for example 115, as a colourlessoil in 20% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.22-1.60 (m, 8H), 1.60-1.73 (m, 2H), 2.43-2.55(m, 2H), 3.14-3.20 (m, 2H), 3.60-3.68 (m, 2H), 4.62-4.73 (m, 1H),5.48-5.62 (br m, 1H), 6.11-6.25 (br m, 1H), 6.26-6.35 (m, 1H), 6.36-6.40(m, 1H), 7.15-7.38 (m, 11H); LRMS APCI m/z 505 [M+H]⁺

EXAMPLE 1405-[3-(3-Bromo-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from the product of preparation 57 andthe product of preparation 89, using a similar method to that describedfor example 99, in 90% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.33-1.40 (m, 2H), 2.42-2.53 (m,2H), 3.06-3.18 (m, 2H), 3.38-3.50 (m, 2H), 3.75 (s, 3H), 4.60-4.66 (m,1H), 6.25 (s, 1H), 6.48 (s, 1H), 6.67 (s, 1H), 7.24-7.46 (m, 10H); LRMSESI m/z 519 [M+H]⁺

EXAMPLE 1415-[3-(3-Bromo-5-methoxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 140, usingthe same method as that described for example 100, as a colourless oilin 80% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12-1.18(m, 2H), 2.38-2.46 (m,2H), 3.05-3.13(m, 2H), 3.37-3.44 (m, 2H), 3.75 (s, 3H), 4.56-4.63 (m,1H), 5.45-5.58 (br m, 1H), 5.95-6.08 (br m, 1H), 6.23 (s, 1H), 6.48 (s,1H), 6.65 (s, 1H), 7.20-7.40 (m, 10H); LRMS ESI m/z 539 [M+H]⁺

EXAMPLE 1425-[3-(3-Bromo-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of example 141, usingthe same method as that described for example 114, as a colourless foamin 27% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.18-1.25 (m, 2H), 2.38-2.46 (m,2H), 3.19-3.26 (m, 2H), 3.55-3.63 (m, 2H), 4.60-4.66 (m, 1H), 5.45-5.58(br m, 1H), 6.13 (s, 1H), 6.20-6.35 (br m, 1H), 6.48 (s, 1H), 6.65 (s,1H), 7.20-7.35 (m, 10H); LRMS ESI m/z 525 [M+H]⁺

EXAMPLE 1434-{1-[3-(3-Fluoro-4-methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyronitrile

The title compound was prepared from the product of preparation 84 and3-fluoro-4-methoxyphenol (J. Het. Chem., 1989, 26, 1547) using a similarmethod to that described for example 99, in 75% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.25-1.39 (m, 2H), 1.40-1.65 (m, 6H), 1.65-1.77(m, 2H), 2.47-2.58 (m, 2H), 3.12-3.22 (m, 2H), 3.46-3.57 (m, 2H), 3.77(s, 3H), 4.66-4.74 (m, 1H), 6.27-6.33 (m, 1H), 6.35-6.43 (m, 1H),6.94-7.03 (m, 1H), 7.24-7.48 (m, 10H); LRMS ESI m/z 485 [M+H]⁺

EXAMPLE 1444-{1-[3-(3-Fluoro-4-methoxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide

The title compound was prepared from the product of example 143, usingthe same method as that described for example 100, as a colourless foamin 65% yield.

¹HNMR(400 MHz, CDCl₃) δ: 1.20-1.37 (m, 4H), 1.39-1.58 (m, 4H), 1.58-1.67(m, 2H), 2.40-2.53 (m, 2H), 3.06-3.15 (m, 2H), 3.46-3.53 (m, 2H), 3.75(s, 3H), 4.60-4.71 (m, 1H), 5.50-5.67 (br m, 1H), 6.17-6.38 (m, 3H),6.88-6.98 (m, 1H), 7.18-7.40 (m, 10H); LRMS APCI m/z 503 [M+H]⁺

EXAMPLE 1454-{1-[3-(3-Fluoro-4-hydroxy-phenoxy)-azetidin-1-yl]-cyclopentyl}-2,2-diphenyl-butyramide

The title compound was prepared from the product of example 144, using asimilar method to that described for example 114, as a colourless foamin 25% yield.

¹HNMR(400 MHz, CDCl₃), δ: 1.31-1.47 (m H, 1.48-1.62 (m, 2H), 1.64-1.78(m, 2H), 2.43-2.54 (m, 2H), 3.27-3.37 (m, 2H), 3.76-3.85 (m, 2H),4.75-4.84 (m, 1H), 5.44-5.56 (br m, 1H), 6.22-6.28 (m, 1H), 6.38-6.44(m, 1H), 6.84-7.00 (m, 2H), 7.16-7.34 (m, 10H).

EXAMPLE 1465-[3-(3-Chloro-4-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The product of preparation 94 (100 mg, 0.19 mmol) was dissolved intetrahydrofuran (10 mL) and sodium borohydride (47 mg, 1.2 mmol) andtetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol) were added.After stirring at 45° C. for 30 minutes, the reaction was cooled to roomtemperature and quenched with a few drops of glacial acetic acid. Thereaction was basified with saturated sodium hydrogen carbonate solution.The organics were extracted with ethyl acetate (20 mL) the organicsolution was dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5,afforded the title compound in 38% yield, 35 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.90 (s, 6H), 1.12-1.20 (m, 2H), 2.38-2.45 (m,2H), 2.98-3.07 (m, 2H), 3.28-3.39 (m, 2H), 4.06-4.15 (m, 1H), 4.26 (s,2H), 5.53-5.65 (br m, 2H), 6.88-6.95 (m, 1H), 7.02-7.06 (m, 1H),7.20-7.37 (m, 11H); LRMS APCI m/z 493 [M+H]⁺

EXAMPLE 1475-[3-(4-Chloro-2-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 98 usinga similar method to that described for example 146, in 19% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12-1.20(m, 2H), 2.40-2.46 (m,2H), 3.04-3.15 (m, 2H), 3.35-3.43 (m, 2H), 4.13-4.20 (m, 1H), 4.47 (s,2H), 5.56-5.74 (br m, 2H), 6.75-6.80 (m, 1H), 7.03 (s, 1H), 7.08-7.14(m, 1H), 7.23-7.38 (m, 10H); LRMS ESI m/z 493 [M+H]⁺

EXAMPLE 1485-[3-(2-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 103using a similar method to that described for example 128, in 25% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.12-124 (m, 2H), 2.38-2.45 (m,2H), 3.02-3.12(m, 2H), 3.28-3.39 (m, 2H), 4.13-4.20 (m, 1H), 4.45 (s,2H), 5.37-5.60 (br m, 2H), 6.94-6.99 (m, 2H), 7.12-7.18 (m, 1H),7.20-7.40 (m, 10H); LRMS APCI m/z 493 [M+H]⁺

EXAMPLE 1495-[3-(3,5-Dihydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

1,3,5-trihydroxybenzene dihydrate (10 g, 79 mmol) was placed in a roundbottomed flask equipped with a Dean Stark trap and dehydrated using 23mL toluene. After removal of the water and concentration in vacuo, thedry phenol was isolated as a white solid.

A mixture of caesium carbonate (107 mg, 0.33 mmol) and anhydrous1,3,5-trihydroxybenzene (125 mg, 0.99 mmol) in N,N-dimethylformamide (3mL) was stirred at 80° C. for 10 minutes. The product of preparation 104(142 mg, 0.33 mmol) was added and the reaction mixture was stirred at80° C. for 10 minutes. The crude material was partitioned between ethylacetate (20 mL) and water (30 mL), the organic layer was separated andthe aqueous re-extracted with ethyl acetate (2×20 mL). The combinedorganics were dried over magnesium sulphate, filtered and concentratedin vacuo. The residue was purified by column chromatography on silicagel, eluting with pentane: (90:10:1 ethyl acetate:methanol:0.88ammonia), 100:1 to 30:70, to afford the title compound as a colourlessgum in 5% yield, 7 mg.

¹HNMR(400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.20-1.28 (m, 2H), 2.35-2.48 (m,2H), 3.15-3.24 (m, 2H), 3.52-3.60 (m, 2H), 4.48-4.58 (m, 1H), 5.62-5.65(br s, 1H), 5.78 (s, 2H), 6.06 (s, 1H), 6.35-6.40 (br s, 1H), 7.15-7.28(m, 10H); LRMS APCI m/z 461[M+H]⁺

EXAMPLE 1505-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile

The title compound was prepared from the product of preparation 105,using the same method as that described in example 109, as a colourlessoil in 73% yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.35-1.40 (m, 2H), 2.42-2.48 (m,2H), 3.16-3.22 (m, 2H), 3.45-3.57 (m, 2H), 4.64-4.72 (m, 1H), 6.25 (s,1H), 6.30-6.35(m, 1H), 6.42-6.48 cm, 1H), 7.05-7.15 (m, 1H), 7.25-7.42(m, 10H); LRMS APCI m/z 427 [M+H]⁺

EXAMPLE 1515-{3-[(4-Hydroxybenzyl)oxy]azetidin-1-yl}-5-methyl-2,2-diphenylhexanenitrile

The title compound was prepared from the products of preparations 56 and66, using the same method as that described for example 101, in 15%yield.

¹HNMR(400 MHz, CDCl₃) δ: 0.95(s, 6H), 1.32-1.40(m, 2H), 2.40-2.48(m,2H), 3.04-3.08(m, 2H), 3.26-3.35(m, 2H), 4.05-4.15(m, 1H), 4.32(s, 2H),6.72-6.76(m, 2H), 7.10-7.15(m, 2H), 7.18-7.46(m, 10H)

EXAMPLE 1525-[3-(4-Hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide

The title compound was prepared from the product of preparation 108using a similar method to that described for example 146, in 53% yield.

¹HNMR(400 MHz, MeOD) δ: 0.95 (s, 6H), 1.23-1.28 (m, 2H), 2.35-2.45 μm,2H), 2.96-3.05 (m, 2H), 3.22-3.28 (m, 2H), 4.01-4.18 (m, 1H), 4.30 (s,2H), 5.55-5.65 (br s, 2H), 6.70-6.75 (m, 2H), 7.05-7.12 (m, 2H),7.20-7.35 (m, 10H); LRMS ESI m/z 459 [M+H]⁺

Potency Assay

M₃ potency was determined in CHO-K1 cells transfected with theNFAT-Betalactamase gene. CHO (Chinese Hamster Ovary) cells recombinantlyexpressing the human muscarinic M₃ receptor were transfected with theNFAT_β-Lac_Zeo plasmid. Cells were grown in DMEM with Glutamax-1,supplemented with 25 mM HEPES (Life Technologies 32430-027), containing10% FCS (Foetal Calf Serum; Sigma F-7524), 1 nM Sodium pyruvate (SigmaS-8636), NEAA (non-Essential Amino Acids; Invitrogen 11140-035) and 200μg/ml Zeocin (Invitrogen R250-01).

hM₃ β-Lac Assay Protocol

Cells were harvested for assay when they reached 80-90% confluency usingenzyme free cell Dissociation Solution (Life technologies 13151-014)incubated with the cells for 5 min at 37° C. in an atmosphere containing5% CO₂. Detached cells were collected in warmed growth media andcentrifuged at 2000 rpm for 10 min, washed in PBS (Phosphate BufferedSaline; Life Technologies 14190-094) and centrifuged again as justdescribed. The cells were re-suspended at 2×10⁵ cells/ml in growthmedium (composition as described above). 20 μl of this cell suspensionwas added to each well of a 384 well black clear bottomed plate (GreinerBio One 781091-PFI). The assay buffer used was PBS supplemented with0.05% Pluronic F-127 (Sigma 9003-11-6) and 2.5% DMSO. Muscarinic M₃receptor signalling was stimulated using 80 nM carbamyl choline (AldrichN240-9) incubated with the cells for 4 h at 37° C./5% CO₂ and monitoredat the end of the incubation period using a Tecan SpectraFluor+ platereader (λ−excitation 405 nm, emission 450 nm and 503 nm). M₃ receptorantagonists under test were added to the assay at the beginning of the 4h incubation period and compound activity measured as the concentrationdependent inhibition of the carbamyl choline induced signal. Inhibitioncurves were plotted and IC₅₀ values generated using a 4-parametersigmoid fit and converted to Ki values using the Cheng-Prusoffcorrection and the K_(D) value for carbamyl choline in the assay.

It has thus been found that carboxamide derivatives of formula (I)according to the present invention that have been tested in the aboveassay show M₃ receptor antagonist activity as listed in the table below:

Cell based Example β-lactamase Number M₃ Ki (nM) 1 8.34 2 0.251 4 1.55 61.02 7 0.212 9 1.87 11 3.27 12 0.300 13 0.512 14 1.32 15 4.25 16 1.85 175.11 18 6.96 19 5.56 20 108 21 0.155 23 0.762 24 20.7 26 1.67 28 47.4 292.26 30 0.333 31 45.1 32 36.4 34 6.57 35 7.28 36 17.6 37 5.01 38 0.99639 1.97 40 6.09 42 22.1 43 5.35 44 32.2 46 1.74 49 48.5 50 3.18 51 0.62352 2.16 53 0.334 54 3.62 58 1580 61 9.85 62 57.4 63 28.7 64 65.6 65 62.766 45.4 67 10.7 68 9.88 69 111 70 19.1 71 113 72 1.23 73 0.852 74 <0.56076 0.582 77 4.96 78 0.917 79 16.2 81 35.4 82 7.96 83 30.0 84 6.97 853.19 86 1.26 88 71.9 89 159 90 0.268 91 22.6 92 2.13 93 26.8 94 12.4 952.25 96 6.51 98 139 99 65.7 100 0.430 102 0.0636 104 0.0488 105 1.94 1070.132 108 0.201 109 10.8 110 7.33 111 76.9 113 7.22 114 1.94 115 0.176118 40.7 121 0.604 124 0.223 127 110 128 8.19 131 0.728 134 0.258 1370.713 138 0.468 139 5.39 142 8.05 145 10.8 146 0.247 147 33.4 148 0.353149 0.714 150 1.05 151 0.191 152 0.229Guinea Pig Trachea Assay

Male, Dinkin-Hartley guinea-pigs weighing 350-450 g are culled in arising concentration of CO₂, followed by exsanguinations of the venacava. Tracheas are dissected from the larynx to the entry point into thechest cavity and then placed in fresh, oxygenated, modified Krebs buffersolution (Krebs containing 10 μM propranolol, 10 μM guanethidine and 3μM indomethacin) at room temperature. The tracheas are opened by cuttingthrough the cartilage opposite the trachealis muscle. Stripsapproximately 3-5 cartilage rings wide are cut. A cotton thread isattached to the cartilage at one end of the strip for attachment to theforce transducer and a cotton loop made at the other end to anchor thetissue in the organ bath. The strips are mounted in 5 ml organ bathsfilled with warm (37° C.) aerated modified Krebs. The pump flow rate isset to 1.0 ml/min and the tissues washed continuously. Tissues areplaced under an initial tension of 1000 mg. Tissues are re-tensionedafter 15 and 30 minutes, then allowed to equilibrate for a further 30-45minutes.

Tissues are subjected to electrical field stimulation (EFS) of thefollowing parameters: 10 s trains every 2 minutes, 0.1 ms pulse width,10 Hz and 10-30V. The voltage is raised 5V every 10 min within thestated range until a maximum contractile response for each tissue isobserved. This just maximum voltage for each tissue is then usedthroughout the remainder of the experiment. Following equilibration toEFS for 20 min, the pump is stopped, and after 15 min control readingsare taken over a 8-10 min period (4-5 responses). Compound is then addedto each tissue as a bolus dose at 30×Ki (determined at the human M₃receptor expressed in CHO cells in a filtration binding assay), and leftto incubate for 2 h. Compound is then washed from tissues using a rapidwash with modified Krebs for 1 min and flow is restored to 1 ml/min forthe remainder of the experiment. At the end of the experiment tissuesare challenged with histamine (1 μM) to determine viability. Readingstaken during the experiment are automatically collected using Notocord®software. The raw data are converted into percent response taking intoaccount measurements of inhibition of the EFS response. After startingwashout, the times taken for the tissue to recover by 25% from theinhibition induced are recorded and used as a measure of compoundduration of action. Tissue viability limits the duration of theexperiment to 16 h post compound washout. Compounds are typically testedat n=2 to 5 to estimate duration of action.

Alternatively the Following Guinea Pig Trachea Assay can Also be Used:

Trachea were removed from male Dunkin-Hartley guinea-pigs (wt 350-450 g)and following removal of adherent connective tissue, an incision wasmade through the cartilage opposite the trachealis muscle and trachealstrips 3-5 cartilage rings wide prepared. The tracheal strips weresuspended between an isometric strain gauge and a fixed tissue hook withthe muscle in the horizontal plane in 5 ml tissue baths under an initialtension of 1 g and bathed in warmed (37° C.) aerated (95% O₂/5% CO₂)Krebs solution containing 3 μM indomethacin and 10 μM guanethidine. Thetissues were positioned between parallel platinum wire electrodes (˜1 cmgap). A constant 1 ml/min flow of fresh Krebs solution (of the abovecomposition) was maintained through the tissue baths using peristalticpumps. The tissues were allowed to equilibrate for an hour withre-tensioning to 1 g at 15 min and 30 min from the start of theequilibration period. At the end of the equilibration, tissues wereelectrically field stimulated (EFS) using the following parameters: 10V,10 Hz 0.1 ms pulse width with 10 sec trains every 2 min. In each tissuea voltage response curve was constructed over the range 10v-30V (keepingall other stimulation parameters constant) to determine a just maximalstimulation. Using these stimulation parameters EFS responses were 100%nerve mediated and 100% cholinergic as confirmed by blockade by 1 μMtetrodotoxin or 1 μM atropine. Tissues were then repeatedly stimulatedat 2 min intervals until the responses were reproducible. Theperistaltic pump was stopped 20 min prior to the addition of the studycompound and the average twitch contraction over the last 10 minrecorded as the control response. The study compound was added to thetissue baths, with each tissue receiving a single concentration ofcompound and allowed to equilibrate for 2 h. At 2 h post addition theinhibition of the EFS response was recorded and IC₅₀ curves generatedusing a range of compound concentrations over tracheal strips from thesame animal. The tissues were then rapidly washed and the 1 ml/minperfusion with Krebs solution re-established. Tissues were stimulatedfor a further 16 h and recovery of the EFS response recorded. At the endof the 16 h, 10 μM histamine was added to the baths to confirm tissueviability. The just max concentration (tested concentration giving aresponse>70% inhibition but less than 100%) of antagonist was identifiedfrom the IC₅₀ curve and the time to 25% recovery of the inducedinhibition (T₂₅) calculated in tissues receiving this concentration.Compounds are typically tested at n=2 to 5 to estimate duration ofaction.

1. A compound of formula (I)

wherein: R¹ is CN or CONH₂; A is selected from

wherein * and ** represent the attachment points, * being linked to thecarbon atom bearing R² and R³ and ** being linked to the oxygen atom; R²and R³ are methyl; or R² and R³ may be taken together with the carbonatom to which they are attached to form a cyclopentane ring; p is 0 or1; A¹ is selected from a) phenyl optionally substituted with 1, 2 or 3groups independently selected from halo, CN, CF₃, OR⁴, SR⁴, OCF₃,(C₁-C₄)alkyl and phenyl optionally substituted with OH; and R⁴ is H or(C₁-C₄)alkyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is CONH₂.
 3. A compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein p is
 0. 4. A compoundaccording to claim 2, or a pharmaceutically acceptable salt thereof,wherein p is
 1. 5. A compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R² and R³ are methyl.6. A compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R² and R³ are methyl and R¹ is CONH₂.
 7. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein A¹ is phenyl optionally substituted with 1, 2 or 3groups independently selected from F, Cl, CF₃, OH, OCH₃, OCF₃and CH₃. 8.A compound according to claim 7, or a pharmaceutically acceptable saltthereof, wherein A¹ is phenyl optionally substituted with 1 or 2 groupsindependently selected from F, Cl, CF₃, OH, OCH₃, OCF₃ and CH₃.
 9. Acompound according to claim 1, said compound being selected from:5-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanamide;5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;5-{3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;5-{3-(3-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;5-{3-(3-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;4-{1[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-cyclopenty}-2,2-diphenyl-butyramide;5-[3-(2-Fluoro-3-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide;5[3-(2-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide; and5-[3-(4-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide; or a pharmaceutically acceptable salt thereof. 10.5[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide ora pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 12. A method of treating adisease, disorder or condition in a subject, said method comprisingadministering to said subject a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof, saiddisease, disorder or condition being selected from the group consistingof chronic or acute bronchoconstriction, small airways obstruction,emphysema, obstructive or inflammatory airways diseases, bronchitis,asthma, acute lung injury and bronchiectasis.
 13. A method of claim 12wherein said disease, disorder or condition is asthma or chronicobstructive pulmonary disease.
 14. A method of claim 13 wherein saidasthma is atopic asthma, non-atopic asthma, allergic asthma, atopicbronchial IgE-mediated asthma, bronchial asthma, essential asthma, trueasthma, intrinsic asthma caused by pathophysiologic disturbances,extrinsic asthma caused by environmental factors, essential asthma ofunknown or inapparent cause, bronchitic asthma, emphysematous asthma,exercise-induced asthma, allergen induced asthma, cold air inducedasthma, occupational asthma, infective asthma caused by bacterial,fungal, protozoal, or viral infection, non-allergic asthma, incipientasthma, wheezy infant syndrome or bronchiolytis.
 15. A method of claim12 wherein said obstructive or inflammatory airways disease is chroniceosinophilic pneumonia, chronic obstructive pulmonary disease (COPD),COPD that includes chronic bronchitis, pulmonary emphysema or dyspneaassociated or not associated with COPD, COPD that is characterized byirreversible, progressive airways obstruction, adult respiratorydistress syndrome (ARDS), exacerbation of airways hyper-reactivityconsequent to other drug therapy or airways disease that is associatedwith pulmonary hypertension.
 16. A method of claim 12 wherein saidbronchitis is chronic bronchitis, acute bronchitis, acutelaryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis,croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis,productive bronchitis, staphylococcus or streptococcal bronchitis orvesicular bronchitis.
 17. The method of claim 12 wherein the compound isselected from the group consisting of:5-Methyl-5-(3-phenoxyazetidin-1-yl)-2,2-diphenylhexanamide;5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;5-{3-(4-Chloro-3-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;5-{3-(3-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;5-{3-(3-Chloro-5-hydroxy-phenoxy)-azetidin-1-yl}-5-methyl-2,2-diphenylhexanamide;4-{1[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-cyclopenty}-2,2-diphenyl-butyramide;5-[3-(2-Fluoro-3-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide;5[3-(2-Fluoro-5-hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide; and,5[3-(4-Chloro-3-hydroxy-benzyloxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoicacid amide; or a pharmaceutically acceptable salt thereof.
 18. Acompound of formula

wherein A is selected from

wherein * and ** represent the attachment points, * being linked to thecarbon bearing R² and R³ and ** being linked to the oxygen atom offormula (I); p is 0 or 1; A¹ is selected from a) phenyl optionallysubstituted with 1, 2 or 3 groups independently selected from halo, CN,CF₃, OR⁴, SR⁴, OCF₃, (C₁-C₄)alkyl and phenyl optionally substituted withOH; and R⁴ is H or (C₁-C₄)alkyl.